ORCID Profile
0000-0003-2309-898X
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Macromolecular and Materials Chemistry | Synthesis of Materials | Cancer Cell Biology | Oncology and Carcinogenesis | Biochemistry and Cell Biology | Colloid and Surface Chemistry | Biomaterials | Therapies And Therapeutic Technology | Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Protein Trafficking | Protein Targeting And Signal Transduction | Cellular Immunology | Pharmacology and Pharmaceutical Sciences | Pharmacology Not Elsewhere Classified | Synthesis Of Macromolecules | Nanotechnology | Biomedical Engineering | Immunological and Bioassay Methods | Genetics | Biotechnology Not Elsewhere Classified | Polymers | Pharmaceutical Sciences | Receptors and Membrane Biology | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Genome Structure and Regulation | Oncology And Carcinogenesis | Nanotechnology | Nanobiotechnology | Cell and Nuclear Division
ANZSRC Socio-Economic Objective (SEO)
Cancer and Related Disorders | Diagnostic Methods | Biological sciences | Other | Health and support services not elsewhere classified | Scientific Instruments | Treatments (e.g. chemicals, antibiotics) | Inherited Diseases (incl. Gene Therapy) | Neurodegenerative Disorders Related to Ageing | Cancer and related disorders | Chemical sciences | Physical sciences | Expanding Knowledge in Technology | Diabetes | Expanding Knowledge in the Biological Sciences | Immune System and Allergy | Infectious Diseases |
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Publications
Movers and shakers: cell cytoskeleton in cancer metastasis
Publisher: Wiley
Date: 02-07-2014
DOI: 10.1111/BPH.12704
Microtubules and resistance to tubulin-binding agents
Publisher: Springer Science and Business Media LLC
Date: 05-03-2010
DOI: 10.1038/NRC2830
TRIM16 Acts as an E3 Ubiquitin Ligase and Can Heterodimerize with Other TRIM Family Members
Publisher: Public Library of Science (PLoS)
Date: 21-05-2012
N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity
Publisher: Springer Science and Business Media LLC
Date: 15-05-2020
DOI: 10.1186/S12935-020-01251-6
Abstract: Drug resistance and chemotherapy-induced peripheral neuropathy continue to be significant problems in the successful treatment of acute lymphoblastic leukemia (ALL). 5,7-Dibromo- N -alkylisatins, a class of potent microtubule destabilizers, are a promising alternative to traditionally used antimitotics with previous demonstrated efficacy against solid tumours in vivo and ability to overcome P-glycoprotein (P-gp) mediated drug resistance in lymphoma and sarcoma cell lines in vitro. In this study, three di-brominated N -alkylisatins were assessed for their ability to retain potency in vincristine (VCR) and 2-methoxyestradiol (2ME2) resistant ALL cell lines. For the first time, in vitro neurotoxicity was also investigated in order to establish their suitability as candidate drugs for future use in ALL treatment. Vincristine resistant (CEM-VCR R) and 2-methoxyestradiol resistant (CEM/2ME2-28.8R) ALL cell lines were used to investigate the ability of N -alkylisatins to overcome chemoresistance. Interaction of N -alkylisatins with tubulin at the the colchicine-binding site was studied by competitive assay using the fluorescent colchicine analogue MTC. Human neuroblastoma SH-SY5Y cells differentiated into a morphological and functional dopaminergic-like neurotransmitter phenotype were used for neurotoxicity and neurofunctional assays. Two-way ANOVA followed by a Tukey’s post hoc test or a two-tailed paired t test was used to determine statistical significance. CEM-VCR R and CEM/2ME2-28.8R cells displayed resistance indices of 100 to VCR and 2-ME2, respectively. CEM-VCR R cells additionally displayed a multi-drug resistant phenotype with significant cross resistance to vinblastine, 2ME2, colchicine and paclitaxel consistent with P-gp overexpression. Despite differences in resistance mechanisms observed between the two cell lines, the N -alkylisatins displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell line. The N -alkylisatins proved to be significantly less neurotoxic towards differentiated SH-SY5Y cells than VCR and vinblastine, evidenced by increased neurite length and number of neurite branch points. Neuronal cells treated with 5,7-dibromo- N -( p -hydroxymethylbenzyl)isatin showed significantly higher voltage-gated sodium channel function than those treated with Vinca alkaloids, strongly supportive of continued action potential firing. The N -alkylisatins are able to retain cytotoxicity towards ALL cell lines with functionally distinct drug resistance mechanisms and show potential for reduced neurotoxicity. As such they pose as promising candidates for future implementation into anticancer regimes for ALL. Further in vivo studies are therefore warranted.
Stathmin levels alter PTPN14 expression and impact neuroblastoma cell migration
Publisher: Springer Science and Business Media LLC
Date: 06-12-2020
DOI: 10.1038/S41416-019-0669-1
Abstract: Stathmin mediates cell migration and invasion in vitro, and metastasis in vivo. To investigate stathmin’s role on the metastatic process, we performed integrated mRNA–miRNA expression analysis to identify pathways regulated by stathmin. MiRNA and gene arrays followed by miRNA-target-gene integration were performed on stathmin-depleted neuroblastoma cells (Ctrl shRNA vs. Stmn Seq2 shRNA ). The expression of the predicted target PTPN14 was evaluated by RT-qPCR, western blot and immunohistochemistry. Gene-silencing technology was used to assess the role of PTPN14 on proliferation, migration, invasion and signalling pathway. Stathmin levels modulated the expression of genes and miRNA in neuroblastoma cells, leading to a deregulation of migration and invasion pathways. Consistent with gene array data, PTPN14 mRNA and protein expression were downregulated in stathmin- depleted neuroblastoma cells and xenografts. In two independent neuroblastoma cells, suppression of PTPN14 expression led to an increase in cell migration and invasion. PTPN14 and stathmin expression did not act in a feedback regulatory loop in PTPN14- depleted cells, suggesting a complex interplay of signalling pathways. The effect of PTPN14 on YAP pathway activation was cell-type dependent. Our findings demonstrate that stathmin levels can regulate PTPN14 expression, which can modulate neuroblastoma cell migration and invasion.
The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs
Publisher: Impact Journals, LLC
Date: 13-10-2016
Partial depletion of gamma-actin suppresses microtubule dynamics.
Publisher: Wiley
Date: 17-01-2013
DOI: 10.1002/CM.21096
Nucleic acid hybridization on an electrically reconfigurable network of gold-coated magnetic nanoparticles enables microRNA detection in blood
Publisher: Springer Science and Business Media LLC
Date: 27-08-2018
DOI: 10.1038/S41565-018-0232-X
Abstract: There is intense interest in quantifying the levels of microRNA because of its importance as a blood-borne biomarker. The challenge has been to develop methods that can monitor microRNA expression both over broad concentration ranges and in ultralow amounts directly in a patient's blood. Here, we show that, through electric-field-induced reconfiguration of a network of gold-coated magnetic nanoparticles modified by probe DNA (DNA-Au@MNPs), it is possible to create a highly sensitive sensor for direct analysis of nucleic acids in s les as complex as whole blood. The sensor is the first to be able to detect concentrations of microRNA from 10 aM to 1 nM in unprocessed blood s les. It can distinguish small variations in microRNA concentrations in blood s les of mice with growing tumours. The ultrasensitive and direct detection of microRNA using an electrically reconfigurable DNA-Au@MNPs network makes the reported device a promising tool for cancer diagnostics.
Monitoring the heterogeneity in single cell responses to drugs using electrochemical impedance and electrochemical noise
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0SC05489E
Abstract: A light addressable single-cell impedance technique for cell adhesion monitoring and measurement of a cell's drug response based on electrochemical noise is introduced.
Dextran-Catechin inhibits angiogenesis by disrupting copper homeostasis in endothelial cells
Publisher: Springer Science and Business Media LLC
Date: 09-08-2017
DOI: 10.1038/S41598-017-07452-W
Abstract: Formation of blood vessels, or angiogenesis, is crucial to cancer progression. Thus, inhibiting angiogenesis can limit the growth and spread of tumors. The natural polyphenol catechin has moderate anti-tumor activity and interacts with copper, which is essential for angiogenesis. Catechin is easily metabolized in the body and this limits its clinical application. We have recently shown that conjugation of catechin with dextran (Dextran-Catechin) improves its serum stability, and exhibits potent anti-tumor activity against neuroblastoma by targeting copper homeostasis. Herein, we investigated the antiangiogenic activity of Dextran-Catechin and its mechanism. We found that Dextran-Catechin displayed potent antiangiogenic activity in vitro and in vivo . We demonstrated Dextran-Catechin generates reactive oxygen species which in turns disrupts copper homeostasis by depleting the copper importer CTR-1 and copper trafficking ATOX-1 protein. Mechanistically, we showed that disrupting copper homeostasis by knockdown of either CTR-1 or ATOX-1 protein can inhibit angiogenesis in endothelial cells. This data strongly suggests the Dextran-Catechin potent antiangiogenic activity is mediated by disrupting copper homeostasis. Thus, compounds such as Dextran-Catechin that affects both tumor growth and angiogenesis could lead the way for development of new drugs against high copper levels tumors.
Perceptions in health and medical research careers: the Australian Society for Medical Research Workforce Survey.
Publisher: AMPCo
Date: 05-2008
DOI: 10.5694/J.1326-5377.2008.TB01766.X
Abstract: To report on the sentiments of the Australian health and medical research (HMR) workforce on issues related to employment and funding opportunities. In August 2006, the Australian Society for Medical Research (ASMR) invited all of its members to participate in an online survey. The survey took the form of a structured questionnaire that focused on career aspirations, career development and training opportunities, attitudes toward moving overseas to work, and employment conditions for medical researchers. Researchers' views on career opportunities, funding opportunities, salary and quality of the working environment impact of these views on retaining a skilled medical research workforce in Australia. Of the 1258 ASMR members, 379 responded (30% response rate). Ninety-six per cent of respondents were currently based in Australia 70% had a PhD or equivalent and 58% were women. Most respondents worked at hospital research centres (37%), independent research institutes (28%) or university departments (24%). Sixty-nine per cent had funding from the National Health and Medical Research Council, with the remainder funded by other sources. Over the previous 5 years, 6% of respondents had left active research and 73% had considered leaving. Factors influencing decisions about whether to leave HMR included shortage of funding (91%), lack of career development opportunities (78%) and poor financial rewards (72%). Fifty-seven per cent of respondents were directly supported by grants or fellowships, with only 16% not reliant on grants for their continuing employment 62% believed that funding had increased over the previous 5 years, yet only 30% perceived an increase in employment opportunities in HMR. Among the respondents, twice as many men as women held postgraduate qualifications and earned >or= dollars 100 000 a year. Employment insecurity and lack of funding are a cause of considerable anxiety among Australian health and medical researchers. This may have important implications for the recruitment and retention of researchers.
Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study
Publisher: Elsevier BV
Date: 04-2016
A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.BCMD.2007.02.009
Abstract: S ling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12 ) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis.
Association of N‐myc amplification with neuroblastoma: The Australian and New Zealand experience
Publisher: Wiley
Date: 02-1992
DOI: 10.1111/J.1440-1754.1992.TB02619.X
Abstract: Tumour s les from 38 patients with neuroblastoma were analysed for the presence of N-myc lification. N-myc gene copy number in tumour DNA was determined by Southern blotting, and by dilution analysis where appropriate. Available clinical data, obtained at tissue collection and by subsequent questionnaire included patient age at diagnosis, catecholamine, ferritin and neuron-specific enolase levels, treatment and disease status. This study was designed to investigate the use of N-myc lification data as an additional indicator for determination of prognosis. Patients with lified N-myc had more rapid disease progression than those without lification (P less than 0.005). Stratification of Stage III and IV patients using N-myc lification permitted identification of a subgroup with poorer prognosis. The results demonstrate that determination of N-myc lification is important in assessment of prognosis and subsequent treatment in patients with neuroblastoma.
Class I β-tubulin mutations in 2-methoxyestradiol-resistant acute lymphoblastic leukemia cells: implications for drug-target interactions
Publisher: American Association for Cancer Research (AACR)
Date: 10-2008
DOI: 10.1158/1535-7163.MCT-08-0442
Abstract: 2-Methoxyestradiol (2ME2) is a naturally occurring derivative of estradiol that has been shown to be an active small molecule that has antitumor and antiangiogenic properties. 2ME2 binds to β-tubulin near the colchicine-binding site, inhibits microtubule polymerization, and induces mitotic arrest. To improve understanding of the mechanisms of action and resistance to 2ME2, we selected leukemia cells, CCRF-CEM, that display increasing resistance to 2ME2, and three of the highly resistant sublines were chosen for detailed analysis. The 2ME2 cells selected in 7.2 to 28.8 μmol/L were found to be 47- to 107-fold resistant to 2ME2 and exhibited low levels of cross-resistance to vinblastine. Two of the lowest 2ME2-resistant sublines were significantly hypersensitive to colchicine and epothilone B, but the hypersensitive effects were lost in the highest 2ME2-resistant subline. Moreover, 2ME2-resistant cells require 10-fold higher concentrations of 2ME2 to induce G2-M cell cycle arrest and have higher amounts of tubulin polymer compared with parental cells. Gene and protein sequencing revealed four class I β-tubulin mutations, S25N, D197N, A248T, and K350N, in the 2ME2-resistant cells. The S25N mutation is within the paclitaxel-binding site, whereas A248T and K350N are within the colchicine-binding site on β-tubulin, yet the resistant cells were not cross-resistant to paclitaxel or colchicine. This strongly suggests that the mutations have induced conformational changes to the binding site that resulted in 2ME2 resistance. The 2ME2-resistant leukemia cells provide novel insights into microtubule stability and drug-target interactions. [Mol Cancer Ther 2008 (9):3150–9]
Acid-Labile Core Cross-Linked Micelles for pH-Triggered Release of Antitumor Drugs
Publisher: American Chemical Society (ACS)
Date: 20-06-2008
DOI: 10.1021/BM800043N
Abstract: Micelles of a model hiphilic block copolymer, poly(hydroxyethyl acrylate)-block-poly(n-butyl acrylate) (PHEA-b-PBA), synthesized via the RAFT polymerization were cross-linked by copolymerization of a degradable cross-linker from the living RAFT-end groups of PBA chains, yielding a cross-linked core without affecting significantly the original micelle size. The cross-linker incorporation into the micelles was evidenced via physicochemical analysis of the copolymer unimers formed upon acidic cleavage of the cross-linked micelles. High doxorubicin loading capacities (60 wt %) were obtained. Hydrolysis of less than half of the cross-links in the core was found to be sufficient to release doxorubicin faster at acidic pH compared to neutral pH. The system represents the first ex le of core-cross-linked micelles that can be destabilized (potentially both above and below CMC) by the pH-dependent cleavage of the cross-links and the subsequent polarity change in the core to enable the release of hydrophobic drugs entrapped inside the micelle.
Targeting Functional Activity of AKT Has Efficacy against Aggressive Neuroblastoma
Publisher: American Chemical Society (ACS)
Date: 23-01-2020
Analyses of tumor burden in vivo and metastasis ex vivo using luciferase-expressing cancer cells in an orthotopic mouse model of neuroblastoma
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3148-4_5
Abstract: Cancer xenograft mouse models are useful for examining and understanding tumor growth and cancer progression in vivo. With the development of bioluminescent imaging, these parameters can now be monitored noninvasively with relative ease. Herein we describe imaging of luciferase-expressing cancer cells to quantitatively measure tumor burden in vivo and metastases ex vivo. Specifically, we detail the methodology to examine the effect of shRNA-mediated knockdown of a target gene on the growth and spread of neuroblastoma tumors in immune-deficient mice.
Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells
Publisher: Informa UK Limited
Date: 17-12-2015
Figure S6 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426425.V1
Abstract: Copper lowering drugs increased NK-mediated cell death in vitro
How can we use the endocytosis pathways to design nanoparticle drug-delivery vehicles to target cancer cells over healthy cells?
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1CS00707F
Abstract: Targeted drug delivery in cancer typically focuses on maximising the endocytosis of drugs into the diseased cells. However, there has been less focus on exploiting the differences in the endocytosis pathways of cancer cells
Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma
Publisher: Oxford University Press (OUP)
Date: 16-09-2003
DOI: 10.1093/JNCI/DJG045
Abstract: Human MYCN (hMYCN) oncogene lification is a powerful predictor of treatment failure in childhood neuroblastoma, and dysregulation of hMYCN protein expression appears to be critically involved in the pathogenesis of this disease. We used hMYCN antisense (AS) oligonucleotides to investigate, both in vitro and in vivo, the therapeutic potential of inhibiting hMYCN expression. We transiently transfected human neuroblastoma IMR-32 cells, which have an lified hMYCN gene, with fluorescently labeled hMYCN AS or scrambled (SCR) control oligonucleotides and used fluorescence-activated cell sorting to enrich for cell populations containing different levels of the oligonucleotides. We used fluorescence immunocytochemistry or reverse transcription polymerase chain reaction to assay gene expression levels and trypan blue exclusion to assay growth inhibition in the cell populations. We examined the effects of continuous treatment for 6 weeks with AS or SCR oligonucleotides via subcutaneously implanted microosmotic pumps on tumor growth in a transgenic mouse model of hMYCN-induced neuroblastoma (n = 20 mice per group). All statistical tests were two-sided. IMR-32 cells treated with AS oligonucleotides had approximately half as much hMYCN protein and cell proliferation as either SCR oligonucleotide-transfected or mock-transfected controls the differences were statistically significant. Transgenic mice treated with AS oligonucleotides had lower tumor incidence and statistically significantly lower tumor mass than SCR-treated or untreated control mice. Compared with control treatments, AS oligonucleotide treatment in vitro and in vivo was associated with decreased expression of hMYCN and putative hMYCN target genes but not with that of closely related genes. Several AS oligonucleotide-treated mice developed tumors contralateral to the site of oligonucleotide administration, whereas SCR oligonucleotide-treated or untreated mice displayed bilateral tumor growth. Decreased expression of hMYCN protein is achievable with the use of AS oligonucleotide treatment, even in the presence of hMYCN oncogene lification. Antisense strategies targeting the hMYCN oncogene in vivo decrease mouse neuroblastoma tumorigenesis. Investigation of their clinical effect in children with neuroblastoma is warranted.
Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1NR02179F
Abstract: Redox-responsive NPs, delivering DTX in combination with TUBB3 siRNA, increased DTX activity in lung cancer (LC) cells. After local administration in LC mice models, NPs were retained into the lungs thus exerting high siRNA silencing efficacy.
Data from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512334
Abstract: Abstract Therapeutic checkpoint antibodies blocking programmed death receptor 1 rogrammed death ligand 1 (PD-L1) signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intratumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the The Cancer Genome Atlas database and tissue microarrays showed strong correlation between the major copper influx transporter copper transporter 1 (CTR-1) and PD-L1 expression across many cancers but not in corresponding normal tissues. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNA sequencing revealed that copper regulates key signaling pathways mediating PD-L1–driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Copper-chelating drugs also significantly increased the number of tumor-infiltrating CD8 sup + /sup T and natural killer cells, slowed tumor growth, and improved mouse survival. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anticancer immunotherapy might be enhanced by pharmacologically reducing intratumor copper levels. Significance: These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity. /
Magnetic catechin–dextran conjugate as targeted therapeutic for pancreatic tumour cells
Publisher: Informa UK Limited
Date: 16-01-2014
Electrostatic Assembly of Multiarm PEG-Based Hydrogels as Extracellular Matrix Mimics: Cell Response in the Presence and Absence of RGD Cell Adhesive Ligands
Publisher: American Chemical Society (ACS)
Date: 24-02-2023
Endothelial cell dysfunction and cytoskeletal changes associated with repression of p16 INK4a during immortalization
Publisher: Springer Science and Business Media LLC
Date: 06-02-2012
DOI: 10.1038/ONC.2011.645
Altered expression of the MYCN oncogene modulates MRP gene expression and response to cytotoxic drugs in neuroblastoma cells.
Publisher: Springer Science and Business Media LLC
Date: 28-04-1999
Abstract: We have recently shown a close correlation between expression of the Multidrug Resistance-associated Protein (MRP) gene and the MYCN oncogene and provided evidence that high MRP expression is a powerful independent predictor of poor outcome in neuroblastoma (Norris et al., New Engl. J. Med., 334, 231-238, 1996). The effect of MYCN down-regulation on MRP expression and response to cytotoxic drugs was investigated in NBL-S neuroblastoma cells transfected with MYCN antisense RNA constructs. Concomitant with MYCN down-regulation, the level of MRP expression was decreased in the NBAS-4 and NBAS-5 antisense transfectants. These cells demonstrated significantly increased sensitivity to the high affinity MRP substrates vincristine, doxorubicin, sodium arsenate and potassium antimony tartrate, but not to the poor MRP substrates, taxol or cisplatin. Similarly, transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in increased MRP expression and significantly increased resistance specifically to MRP substrates. The results provide evidence for the MYCN oncogene influencing cytotoxic drug response via regulation of MRP gene expression. Our data also provide a link between the malignant and chemoresistant phenotypes of this childhood malignancy.
Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/ONC.2016.220
Abstract: Neuroblastoma, the most common solid tumor of young children, frequently presents with aggressive metastatic disease and for these children the 5-year survival rates are dismal. Metastasis, the movement of cancer cells from one site to another, involves remodeling of the cytoskeleton including altered microtubule dynamics. The microtubule-destabilizing protein, stathmin, has recently been shown to mediate neuroblastoma metastasis although precise functions remain poorly defined. In this study we investigated stathmin's contribution to the metastatic process and potential mechanism(s) by which it exerts these effects. Stathmin suppression significantly reduced neuroblastoma cell invasion of 3D tumor spheroids into an extracellular matrix. Moreover, inhibiting stathmin expression significantly reduced transendothelial migration in two different neuroblastoma cell lines in vitro. Inhibition of ROCK, a key regulator of cell migration, in neuroblastoma cells highlighted that stathmin regulates transendothelial migration through ROCK signaling. Reduced stathmin expression in neuroblastoma cells significantly increased the activation of the RhoA small GTPase. Notably, re-expression of either wild type or a phospho-mimetic stathmin mutant (4E) made defective in tubulin binding returned cell migration and transendothelial migration back to control levels, indicating that stathmin may influence these processes in neuroblastoma cells independent of tubulin binding. Finally, stathmin suppression in neuroblastoma cells significantly reduced whole body, lung, kidney and liver metastases in an experimental metastases mouse model. In conclusion, stathmin suppression interferes with the metastatic process via RhoA/ROCK signaling in neuroblastoma cells. These findings highlight the importance of stathmin to the metastatic process and its potential as a therapeutic target for the treatment of neuroblastoma.
Advances in 3D Bioprinting for Cancer Biology and Precision Medicine: From Matrix Design to Application.
Publisher: Wiley
Date: 15-08-2022
Abstract: The tumor microenvironment is highly complex owing to its heterogeneous composition and dynamic nature. This makes tumors difficult to replicate using traditional 2D cell culture models that are frequently used for studying tumor biology and drug screening. This often leads to poor translation of results between in vitro and in vivo and is reflected in the extremely low success rates of new candidate drugs delivered to the clinic. Therefore, there has been intense interest in developing 3D tumor models in the laboratory that are representative of the in vivo tumor microenvironment and patient s les. 3D bioprinting is an emerging technology that enables the biofabrication of structures with the virtue of providing accurate control over distribution of cells, biological molecules, and matrix scaffolding. This technology has the potential to bridge the gap between in vitro and in vivo by closely recapitulating the tumor microenvironment. Here, a brief overview of the tumor microenvironment is provided and key considerations in biofabrication of tumor models are discussed. Bioprinting techniques and choice of bioinks for both natural and synthetic polymers are also outlined. Lastly, current bioprinted tumor models are reviewed and the perspectives of how clinical applications can greatly benefit from 3D bioprinting technologies are offered.
TUBB3/βIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2015
DOI: 10.1158/0008-5472.CAN-14-2740
Abstract: βIII-tubulin (encoded by TUBB3) expression is associated with therapeutic resistance and aggressive disease in non–small cell lung cancer (NSCLC), but the basis for its pathogenic influence is not understood. Functional and differential proteomics revealed that βIII-tubulin regulates expression of proteins associated with malignant growth and metastases. In particular, the adhesion-associated tumor suppressor maspin was differentially regulated by βIII-tubulin. Functionally, βIII-tubulin suppression altered cell morphology, reduced tumor spheroid outgrowth, and increased sensitivity to anoikis. Mechanistically, the PTEN/AKT signaling axis was defined as a critical pathway regulated by βIII-tubulin in NSCLC cells. βIII-Tubulin blockage in vivo reduced tumor incidence and growth. Overall, our findings revealed how βIII-tubulin influences tumor growth in NSCLC, defining new biologic functions and mechanism of action of βIII-tubulin in tumorigenesis. Cancer Res 75(2) 415–25. ©2014 AACR.
βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells.
Publisher: Wiley
Date: 10-08-2022
DOI: 10.1002/CAM4.5128
Abstract: Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of sensitising tumour cells to therapeutic agents. βIII-tubulin is associated with aggressive tumours and chemotherapy resistance in a range of cancers including NSCLC. βIII-tubulin expression has been shown to impact kinase signalling in NSCLC cells. Here, we sought to exploit this interaction by identifying co-activity between βIII-tubulin suppression and small-molecule kinase inhibitors. To achieve this, a forced-genetics approach combined with a high-throughput drug screen was used. We show that activity of the multi-kinase inhibitor Amuvatinib (MP-470) is enhanced by βIII-tubulin suppression in independent NSCLC cell lines. We also show that this compound significantly inhibits cell proliferation among βIII-tubulin knockdown cells expressing the receptor tyrosine kinase c-Met. Together, our results highlight that βIII-tubulin suppression combined with targeting specific receptor tyrosine kinases may represent a novel therapeutic approach for otherwise difficult-to-treat lung carcinomas.
Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells
Publisher: Springer Science and Business Media LLC
Date: 10-11-2012
Master Regulator Analysis from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426419.V1
Abstract: Methods for Master Regulator Analysis
Evolution of resistance to Aurora kinase B inhibitors in leukaemia cells.
Publisher: Public Library of Science (PLoS)
Date: 16-02-2012
Metronomic chemotherapy regimens using Microtubule-targeting agents: Mechanisms of action, preclinical activity and future developments
Publisher: Springer Berlin Heidelberg
Date: 2014
βIII-Tubulin Is a Multifunctional Protein Involved in Drug Sensitivity and Tumorigenesis in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 14-06-2010
DOI: 10.1158/0008-5472.CAN-09-4487
Abstract: Advanced non–small cell lung cancer (NSCLC) has a dismal prognosis. βIII-Tubulin, a protein highly expressed in neuronal cells, is strongly associated with drug-refractory and aggressive NSCLC. To date, the role of this protein in in vivo drug resistance and tumorigenesis has not been determined. NSCLC cells stably expressing βIII-tubulin short hairpin RNA displayed reduced growth and increased chemotherapy sensitivity when compared with control clones. In concordance with these results, stable suppression of βIII-tubulin reduced the incidence and significantly delayed the growth of tumors in mice relative to controls. Our findings indicate that βIII-tubulin mediates not only drug sensitivity but also the incidence and progression of lung cancer. βIII-Tubulin is a cellular survival factor that, when suppressed, sensitizes cells to chemotherapy via enhanced apoptosis induction and decreased tumorigenesis. Findings establish that upregulation of a neuronal tubulin isotype is a key contributor to tumor progression and drug sensitivity in lung adenocarcinoma. Cancer Res 70(12) 4995–5003. ©2010 AACR.
Effective Delivery of siRNA into Cancer Cells and Tumors Using Well-Defined Biodegradable Cationic Star Polymers
Publisher: American Chemical Society (ACS)
Date: 06-05-2013
DOI: 10.1021/MP400049E
Abstract: Cancer is one of the most common causes of death worldwide. Two types of cancer that have high mortality rates are pancreatic and lung cancer. Despite improvements in treatment strategies, resistance to chemotherapy and the presence of metastases are common. Therefore, novel therapies which target and silence genes involved in regulating these processes are required. Short-interfering RNA (siRNA) holds great promise as a therapeutic to silence disease-causing genes. However, siRNA requires a delivery vehicle to enter the cell to allow it to silence its target gene. Herein, we report on the design and synthesis of cationic star polymers as novel delivery vehicles for siRNA to silence genes in pancreatic and lung cancer cells. Dimethylaminoethyl methacrylate (DMAEMA) was polymerized via reversible addition-fragmentation transfer polymerization (RAFT) and then chain extended in the presence of both cross-linkers N,N-bis(acryloyl)cistamine and DMAEMA, yielding biodegradable well-defined star polymers. The star polymers were characterized by transmission electron microscopy, dynamic light scattering, ζ potential, and gel permeation chromatography. Importantly, the star polymers were able to self-assemble with siRNA and form small uniform nanoparticle complexes. Moreover, the ratios of star polymer required to complex siRNA were nontoxic in both pancreatic and lung cancer cells. Treatment with star polymer-siRNA complexes resulted in uptake of siRNA into both cell lines and a significant decrease in target gene mRNA and protein levels. In addition, delivery of clinically relevant amounts of siRNA complexed to the star polymer were able to silence target gene expression by 50% in an in vivo tumor setting. Collectively, these results provide the first evidence of well-defined small cationic star polymers to deliver active siRNA to both pancreatic and lung cancer cells and may be a valuable tool to inhibit key genes involved in promoting chemotherapy drug resistance and metastases.
β-Tubulin carboxy-terminal tails exhibit isotype-specific effects on microtubule dynamics in human gene-edited cells
Publisher: Life Science Alliance, LLC
Date: 19-04-2018
Abstract: Microtubules are highly dynamic structures that play an integral role in fundamental cellular functions. Different α- and β-tubulin isotypes are thought to confer unique dynamic properties to microtubules. The tubulin isotypes have highly conserved structures, differing mainly in their carboxy-terminal (C-terminal) tail sequences. However, little is known about the importance of the C-terminal tail in regulating and coordinating microtubule dynamics. We developed syngeneic human cell models using gene editing to precisely modify the β-tubulin C-terminal tail region while preserving the endogenous microtubule network. Fluorescent microscopy of live cells, coupled with advanced image analysis, revealed that the β-tubulin C-terminal tails differentially coordinate the collective and in idual dynamic behavior of microtubules by affecting microtubule growth rates and explorative microtubule assembly in an isotype-specific manner. Furthermore, βI- and βIII-tubulin C-terminal tails differentially regulate the sensitivity of microtubules to tubulin-binding agents and the microtubule depolymerizing protein mitotic centromere-associated kinesin. The sequence of the β-tubulin tail encodes regulatory information that instructs and coordinates microtubule dynamics, thereby fine-tuning microtubule dynamics to support cellular functions.
High temporal resolution RNA-seq time course data reveals mammalian lncRNA activation mirrors neighbouring protein-coding genes
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2021
DOI: 10.1101/2021.08.25.457323
Abstract: The advent of next-generation sequencing revealed extensive transcription beyond protein-coding genes, identifying tens of thousands of long non-coding RNAs (lncRNAs). Selected functional ex les raised the possibility that lncRNAs, as a class, may maintain broad regulatory roles. Compellingly, lncRNA expression is strongly linked with adjacent protein-coding gene expression, suggesting a potential cis -regulatory function. Evidence for these regulatory roles may be obtained through careful examination of the precise timing of lncRNA expression relative to adjacent protein-coding genes. Where causal cis -regulatory relationships exist, lncRNA activation is expected to precede changes in adjacent target gene expression. Using an RNA-seq time course of uniquely high temporal resolution, we profiled the expression dynamics of several thousand lncRNAs and protein-coding genes in synchronized, transitioning human cells. Our findings reveal lncRNAs are expressed synchronously with adjacent protein-coding genes. Analysis of lipopolysaccharide-activated mouse dendritic cells revealed the same temporal relationship observed in transitioning human cells. Our findings suggest broad-scale cis -regulatory roles for lncRNAs are not common. The strong association between lncRNAs and adjacent genes may instead indicate an origin as transcriptional by-products from active protein-coding gene promoters and enhancers.
Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.CCELL.2020.05.014
Abstract: Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2PY20112G
Class III β-tubulin mediates sensitivity to chemotherapeutic drugs in non-small cell lung cancer
Publisher: American Association for Cancer Research (AACR)
Date: 10-2007
DOI: 10.1158/0008-5472.CAN-07-0509
Abstract: First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III β-tubulin (βIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of βIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that βIII-siRNA potently inhibited the expression of βIII-tubulin, without affecting the expression of other major β-tubulin isotypes. Clonogenic assays showed that βIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 βIII-siRNA cells showed reduced accumulation at the G2-M boundary and an increase in the sub-G1 population in response to TBA treatment compared with control cells. Importantly, βIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for βIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007 (19):9356–63]
Microtubules and Their Role in Cellular Stress in Cancer
Publisher: Frontiers Media SA
Date: 18-06-2014
A high-throughput 3D bioprinted cancer cell migration and invasion model with versatile and broad biological applicability
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2021
DOI: 10.1101/2021.12.28.474387
Abstract: Understanding the underlying mechanisms of migration and metastasis is a key focus of cancer research. There is an urgent need to develop in vitro 3D tumor models that can mimic physiological cell-cell and cell-extracellular matrix interactions, with high reproducibility and that are suitable for high throughput (HTP) drug screening. Here, we developed a HTP 3D bioprinted migration model using a bespoke drop-on-demand bioprinting platform. This HTP platform coupled with tunable hydrogel systems enables (i) the rapid encapsulation of cancer cells within in vivo tumor mimicking matrices, (ii) in situ and real-time measurement of cell movement, (iii) detailed molecular analysis for the study of mechanisms underlying cell migration and invasion, and (iv) the identification of novel therapeutic options. This work demonstrates that this HTP 3D bioprinted cell migration platform has broad applications across quantitative cell and cancer biology as well as drug screening.
Intracellular nitric oxide delivery from stable NO-polymeric nanoparticle carriers
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2CC37181B
Abstract: The encapsulation of S-nitrosoglutathione into polymeric nanoparticles substantially improves NO stability in aqueous media without affecting the efficacy of intracellular delivery. The combination of nano-NO delivery and chemotherapy has been found to enhance antitumour activity of chemotherapeutics, as demonstrated using preliminary in vitro experiments with neuroblastoma cells.
Potential mechanisms of resistance to microtubule inhibitors.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1053/J.SEMINONCOL.2008.01.006
Abstract: Antimitotic drugs targeting the microtubules, such as the taxanes and vinca alkaloids, are widely used in the treatment of neoplastic diseases. Development of drug resistance over time, however, limits the efficacy of these agents and poses a clinical challenge to long-term improvement of patient outcomes. Understanding the mechanism(s) of drug resistance becomes paramount to allowing for alternative, if not improved, therapeutic options that might circumvent this challenge. Vinflunine, a novel microtubule inhibitor, has shown superior preclinical antitumor activity, and displays a different pattern of resistance, compared with other agents in the vinca alkaloid class.
Figure S1 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426440
Abstract: Co-expression plots of VST-normalized gene expression profiles derived from TCGA datasets for PD-L1 and four copper-responsive genes
γ-Actin plays a key role in endothelial cell motility and neovessel maintenance
Publisher: Publiverse Online S.R.L
Date: 2015
Efficient functionalisation of dextran-aldehyde with catechin: potential applications in the treatment of cancer
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6PY00228E
Abstract: Dextran aldehyde was functionalised with up to 38 wt% catechin and the resulting conjugate demonstrated cytotoxic efficacy against neuroblastoma cells.
Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth
Publisher: Impact Journals, LLC
Date: 21-06-2016
Manganese-Based Magnetic Layered Double Hydroxide Nanoparticle: A pH-Sensitive and Concurrently Enhanced T1/T2-Weighted Dual-Mode Magnetic Resonance Imaging Contras
Publisher: American Chemical Society (ACS)
Date: 25-03-2019
Computational analysis of image‐based drug profiling predicts synergistic drug combinations: Applications in triple‐negative breast cancer
Publisher: Wiley
Date: 19-06-2014
γ‐Actin regulates cell migration and modulates the ROCK signaling pathway
Publisher: Wiley
Date: 09-09-2011
DOI: 10.1096/FJ.11-185447
Abstract: Cell migration plays a crucial role in numerous cellular functions, and alterations in the regulation of cell migration are required for invasive transformation of a tumor cell. While the mechanistic process of actin-based migration has been well documented, little is known as to the specific function of the nonmuscle actin isoforms in mammalian cells. Here, we present a comprehensive examination of γ-actin's role in cell migration using an RNAi approach. The partial suppression of γ-actin expression in SH-EP neuroblastoma cells resulted in a significant decrease in wound healing and transwell migration. Similarly, the knockdown of γ-actin significantly reduced speed of motility and severely affected the cell's ability to explore, which was, in part, due to a loss of cell polarity. Moreover, there was a significant increase in the size and number of paxillin-containing focal adhesions, coupled with a significant decrease in phosphorylated paxillin in γ-actin-knockdown cells. In addition, there was a significant increase in the phosphorylation of cofilin and myosin regulatory light chain, suggesting an overactivated Rho-associated kinase (ROCK) signaling pathway in γ-actin-knockdown cells. The alterations in the phosphorylation of paxillin and myosin regulatory light chain were unique to γ-actin and not β-actin knockdown. Inhibition of the ROCK pathway with the inhibitor Y-27632 restored the ability of γ-actin-knockdown cells to migrate. This study demonstrates γ-actin as a potential upstream regulator of ROCK mediated cell migration.
Tissue-specific Tropomyosin Isoform Composition
Publisher: SAGE Publications
Date: 05-2005
Abstract: Four distinct genes encode tropomyosin (Tm) proteins, integral components of the actin microfilament system. In non-muscle cells, over 40 Tm isoforms are derived using alternative splicing. Distinct populations of actin filaments characterized by the composition of these Tm isoforms are found differentially sorted within cells ( Gunning et al. 1998b ). We hypothesized that these distinct intracellular compartments defined by the association of Tm isoforms may allow for independent regulation of microfilament function. Consequently, to understand the molecular mechanisms that give rise to these different microfilaments and their regulation, a cohort of fully characterized isoform-specific Tm antibodies was required. The characterization protocol initially involved testing the specificity of the antibodies on bacterially produced Tm proteins. We then confirmed that these Tm antibodies can be used to probe the expression and subcellular localization of different Tm isoforms by Western blot analysis, immunofluorescence staining of cells in culture, and immunohistochemistry of paraffin wax-embedded mouse tissues. These Tm antibodies, therefore, have the capacity to monitor specific actin filament populations in a range of experimental systems.
Erratum: Microtubules and resistance to tubulin-binding agents (Nature Reviews Cancer)
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NRC2819
Abstract: MYC regulates the transcription of thousands of genes required to coordinate a range of cellular processes, including those essential for proliferation, growth, differentiation, apoptosis and self-renewal. Recently, MYC has also been shown to serve as a direct regulator of ribosome biogenesis. MYC coordinates protein synthesis through the transcriptional control of RNA and protein components of ribosomes, and of gene products required for the processing of ribosomal RNA, the nuclear export of ribosomal subunits and the initiation of mRNA translation. We discuss how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.
Figure S2 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426437
Abstract: Effect of copper levels on PD-L1 expression and interferon stimulation in cancer cells
Microtubule alterations and mutations induced by desoxyepothilone B: Implications for drug-target interactions
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S1074-5521(03)00141-8
Abstract: Epothilones, like paclitaxel, bind to beta-tubulin and stabilize microtubules. We selected a series of four leukemia sublines that display increasing levels of resistance to the epothilone analog desoxyepothilone B (dEpoB). The dEpoB cells selected in 30-140 nM were approximately 15-fold cross-resistant to paclitaxel, while 300 nM selected cells were 467-fold resistant to this agent. The dEpoB-selected cells are hypersensitive to microtubule destabilizing agents, and express increased levels of class III beta-tubulin and MAP4. A novel class I beta-tubulin mutation, A231T, that affects microtubule stability but does not alter paclitaxel binding, was identified. The 300 nM selected cells acquired a second mutation, Q292E, situated near the M loop of class I beta-tubulin. These cells fail to undergo drug-induced tubulin polymerization due to dramatically reduced drug binding. The dEpoB-resistant leukemia cells provide novel insights into microtubule dynamics and, in particular, drug-target interactions.
Figure S3 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426434
Abstract: Effect of copper levels on EGFR phosphorylation and PD-L1 protein stability
Figure S4 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426431
Abstract: TEPA increases tumor-infiltrating immune cells in Th-MYCN mice
A covalently crosslinked bioink for multi-materials drop-on-demand 3D bioprinting of three-dimensional cell cultures
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2021
DOI: 10.1101/2021.02.18.431759
Abstract: In vitro three-dimensional (3D) cell models have been accepted to better recapitulate aspects of in vivo organ environment than 2D cell culture. Currently, the production of these complex in vitro 3D cell models with multiple cell types and microenvironments remains challenging and prone to human error. Here we report a versatile bioink comprised of a 4-arm PEG based polymer with distal maleimide derivatives as the main ink component and a bis-thiol species as the activator that crosslinks the polymer to form the hydrogel in less than a second. The rapid gelation makes the polymer system compatible with 3D bioprinting. The ink is combined with a drop-on-demand 3D bioprinting platform consisting of eight independently addressable nozzles and high-throughput printing logic for creating complex 3D cell culture models. The combination of multiple nozzles and fast printing logic enables the rapid preparation of many complex 3D structures comprising multiple hydrogel environments in the one structure in a standard 96-well plate format. The platform compatibility for biological applications was validated using pancreatic ductal adenocarcinoma cancer (PDAC) cells with their phenotypic responses controlled by tuning the hydrogel microenvironment.
Resistance to Drugs Associated With the Multidrug Resistance Phenotype Following Selection With High-Concentration Methotrexate
Publisher: Oxford University Press (OUP)
Date: 16-08-1989
Abstract: To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.
The retinoid signalling molecule, TRIM16, is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro
Publisher: Wiley
Date: 18-10-2011
DOI: 10.1002/PATH.2986
Nanotechnology in Medical Research
Publisher: Elsevier
Date: 2017
An assay for the determination of reduced methotrexate accumulation in cells displaying limited viability in vitro
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/0304-3835(95)03950-2
Abstract: Amongst the mechanisms known to mediate resistance to methotrexate (MTX), a major component in the treatment of childhood leukemia, reduced drug accumulation appears to have direct clinical relevance. However, due to the poor viability of patient-derived acute lymphoblastic leukemia cells in vitro, determination of this parameter in clinical s les is associated with a number of difficulties. We have therefore developed an assay for reduced MTX accumulation, which controls for the metabolic state of the cell population under study by utilizing accumulation of the nucleoside thymidine as an independent indicator of this parameter. To establish this assay, we have utilized pediatric leukemic cell populations maintained as xenografts in nude mice, which, despite displaying sensitivity to MTX, demonstrated reduced accumulation of MTX when assayed using standard methodology. When accumulation of MTX by such cell populations was expressed, however, relative to their accumulation of thymidine, MTX accumulation was shown to be equal to that of drug-sensitive CCRF-CEM cells maintained in long-term culture. In contrast, significantly less MTX was accumulated, in this assay, by xenografted cell populations with demonstrated resistance to MTX. Identical results were obtained using either fresh or cryopreserved cells. The data thus indicate that by controlling for variable metabolic status of leukemic cells, it is possible to accurately assess MTX accumulation in leukemic s les displaying limited viability in culture.
Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer
Publisher: Impact Journals, LLC
Date: 06-01-2015
Abstract: Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide due its resistance to chemotherapy and aggressive tumor growth. Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in cancer cells, and plays a major role in regulating tumor growth. A number of PLK1 inhibitors are in clinical trial however, poor tumor bioavailability and off-target effects limit their efficacy. Short-interfering-RNA (siRNA) holds promise as a class of therapeutics, which can selectively silence disease-causing genes. However, siRNA cannot enter cells without a delivery vehicle. Herein, we investigated whether RNAi-interfering nanoparticles could deliver siRNA to NSCLC cells and silence PLK1 expression in vitro and in vivo. iNOP-7 was non-toxic, and delivered siRNA with high efficiency to NSCLC cells. iNOP-7-PLK1 siRNA silenced PLK1 expression and reduced NSCLC growth in vitro. Notably, iNOP-7 delivered siRNA to orthotopic lung tumors in mice, and administration of iNOP-7-PLK1 siRNA reduced lung tumor burden. These novel data show that iNOP-7 can deliver siRNA against PLK1 to NSCLC cells, and decrease cell proliferation both in vitro and in vivo. iNOP-7-PLK1 siRNA may provide a novel therapeutic strategy for the treatment of NSCLC as well as other cancers which aberrantly express this gene.
Choice of Capping Group in Tripeptide Hydrogels Influences Viability in the Three‐Dimensional Cell Culture of Tumor Spheroids
Publisher: Wiley
Date: 07-12-2017
Abstract: Two peptide-derived low-molecular-weight gelators bearing different capping groups, 9-fluorenylmethyloxycarbonyl (Fmoc) and phenothiazine, were synthesized and their gel networks were characterized. The variation of the N-terminal capping group affects the viability of these hydrogels as a three-dimensional cell culture for multicellular tumor spheroids. These results indicate that the phenothiazine capping group is a more biocompatible alternative to the widely used Fmoc moiety.
A crisis in the making? Education, ageing populations and the future of the medical research workforce
Publisher: Wiley
Date: 05-01-2011
DOI: 10.1111/J.1365-2923.2010.03785.X
Abstract: this study aims to project attrition from the Australian health and medical research workforce for those aged > 40 years in 2009, through to 2019, and to draw conclusions about the future of this workforce and the international implications of ageing workforce populations. the study uses recently collected unpublished demographic data on the 2009 health and medical research workforce drawn from an Australian Society for Medical Research survey of health and medical research organisations. about 6250 members of the health and medical research workforce aged > 40 years in 2009 are expected to leave the workforce during 2009-2019 the bulk of these will be aged 50-69 years. It is estimated that 35% of women and 49% of men aged 40-49 years in 2009 will retire by the age of 50-59 years, and 85% of women and 70% of men aged 50-59 years in 2009 are also projected to retire over the next 10 years. Of the 6250 members who are expected to leave the workforce by 2019, about 4000 hold a PhD. As a result of population growth, a further 1700 persons with a PhD will be required if Australia is to maintain its current ratio of PhD-qualified persons in the health and medical research workforce: working population to 2019, at a cost of about AU$240 million. there is a need to plan for the replacement of the retiring generation of the health and medical research workforce and for the growth required to match that of the working population. If Australia is to fulfil its ambition for a highly educated, optimally skilled and highly trained health and medical research sector, it must heighten its focus on the higher education of young medical researchers. As population ageing is an emerging phenomenon worldwide, all first world nations are likely to face the challenges involved in replacing a rapidly retiring generation of the health and medical research workforce.
Targeted doxorubicin-loaded bacterially derived nano-cells for the treatment of neuroblastoma
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2018
DOI: 10.1158/1535-7163.MCT-17-0738
Abstract: Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDVTM) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high SH-SY-5Y, low] were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EGFREDVTM. In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox-treated animals compared to control, doxorubicin, or non-EGFR EDVTMDox. There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDVTMDox. Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P & 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther 17(5) 1012–23. ©2018 AACR.
Aerosol delivery of star polymer-siRNA nanoparticles as a therapeutic strategy to inhibit lung tumor growth
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BIOMATERIALS.2022.121539
Abstract: Lung cancer is a major contributor to cancer-related death worldwide. siRNA nanomedicines are powerful tools for cancer therapeutics. However, there are challenges to overcome to increase siRNA delivery to solid tumors, including penetration of nanoparticles into a complex microenvironment following systemic delivery while avoiding rapid clearance by the reticuloendothelial system, and limited siRNA release from endosomes once inside the cell. Here we characterized cell uptake, intracellular trafficking, and gene silencing activity of miktoarm star polymer (PDMAEMA-POEGMA) nanoparticles (star nanoparticles) complexed to siRNA in lung cancer cells. We investigated the potential of nebulized star-siRNA nanoparticles to accumulate into orthotopic mouse lung tumors to inhibit expression of two genes [βIII-tubulin, Polo-Like Kinase 1 (PLK1)] which: 1) are upregulated in lung cancer cells 2) promote tumor growth and 3) are difficult to inhibit using chemical drugs. Star-siRNA nanoparticles internalized into lung cancer cells and escaped the endo-lysosomal pathway to inhibit target gene expression in lung cancer cells in vitro. Nebulized star-siRNA nanoparticles accumulated into lungs and silenced the expression of βIII-tubulin and PLK1 in mouse lung tumors, delaying aggressive tumor growth. These results demonstrate a proof-of-concept for aerosol delivery of star-siRNA nanoparticles as a novel therapeutic strategy to inhibit lung tumor growth.
Macromolecular Hydrogen Sulfide Donors Trigger Spatiotemporally Confined Changes in Cell Signaling
Publisher: American Chemical Society (ACS)
Date: 23-12-2016
DOI: 10.1021/ACS.BIOMAC.5B01469
Abstract: Hydrogen sulfide (H2S) is involved in a myriad of cell signaling processes that trigger physiological events ranging from vasodilation to cell proliferation. Moreover, disturbances to H2S signaling have been associated with numerous pathologies. As such, the ability to release H2S in a cellular environment and stimulate signaling events is of considerable interest. Herein we report the synthesis of macromolecular H2S donors capable of stimulating cell signaling pathways in both the cytosol and at the cell membrane. Specifically, copolymers having pendent oligo(ethylene glycol) and benzonitrile groups were synthesized, and the benzonitrile groups were subsequently transformed into primary aryl thioamide groups via thionation using sodium hydrosulfide. These thioamide moieties could be incorporated into a hydrophilic copolymer or a block copolymer (i.e., into either the hydrophilic or hydrophobic domain). An electrochemical sensor was used to demonstrate release of H2S under simulated physiological conditions. Subsequent treatment of HEK293 cells with a macromolecular H2S donor elicited a slow and sustained increase in cytosolic ERK signaling, as monitored using a FRET-based biosensor. The macromolecular donor was also shown to induce a small, fast and sustained increase in plasma membrane-localized PKC activity immediately following addition to cells. Studies using an H2S-selective fluorescent probe in live cells confirmed release of H2S from the macromolecular donor over physiologically relevant time scales consistent with the signaling observations. Taken together, these results demonstrate that by using macromolecular H2S donors it is possible to trigger spatiotemporally confined cell signaling events. Moreover, the localized nature of the observed signaling suggests that macromolecular donor design may provide an approach for selectively stimulating certain cellular biochemical pathways.
6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 2017
DOI: 10.1158/1535-7163.MCT-16-0325
Abstract: The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell isions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA–treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. Mol Cancer Ther 16(1) 3–15. ©2016 AACR.
Block Co-polymer Nanoparticles with Degradable Cross-Linked Core and Low-Molecular-Weight PEG Corona for Anti-tumour Drug Delivery
Publisher: Informa UK Limited
Date: 2011
RNAi-mediated stathmin suppression reduces lung metastasis in an orthotopic neuroblastoma mouse model
Publisher: Springer Science and Business Media LLC
Date: 11-02-2013
DOI: 10.1038/ONC.2013.11
Abstract: Metastatic neuroblastoma is an aggressive childhood cancer of neural crest origin. Stathmin, a microtubule destabilizing protein, is highly expressed in neuroblastoma although its functional role in this malignancy has not been addressed. Herein, we investigate stathmin's contribution to neuroblastoma tumor growth and metastasis. Small interfering RNA (siRNA)-mediated stathmin suppression in two independent neuroblastoma cell lines, BE(2)-C and SH-SY5Y, did not markedly influence cell proliferation, viability or anchorage-independent growth. In contrast, stathmin suppression significantly reduced cell migration and invasion in both the neuroblastoma cell lines. Stathmin suppression altered neuroblastoma cell morphology and this was associated with changes in the cytoskeleton, including increased tubulin polymer levels. Stathmin suppression also modulated phosphorylation of the actin-regulatory proteins, cofilin and myosin light chain (MLC). Treatment of stathmin-suppressed neuroblastoma cells with the ROCKI and ROCKII inhibitor, Y-27632, ablated MLC phosphorylation and returned the level of cofilin phosphorylation and cell invasion back to that of untreated control cells. ROCKII inhibition (H-1152) and siRNA suppression also reduced cofilin phosphorylation in stathmin-suppressed cells, indicating that ROCKII mediates stathmin's regulation of cofilin phosphorylation. This data demonstrates a link between stathmin and the regulation of cofilin and MLC phosphorylation via ROCK. To examine stathmin's role in neuroblastoma metastasis, stathmin short hairpin RNA (shRNA)\\luciferase-expressing neuroblastoma cells were injected orthotopically into severe combined immunodeficiency-Beige mice, and tumor growth monitored by bioluminescent imaging. Stathmin suppression did not influence neuroblastoma cell engraftment or tumor growth. In contrast, stathmin suppression significantly reduced neuroblastoma lung metastases by 71% (P<0.008) compared with control. This is the first study to confirm a role for stathmin in hematogenous spread using a clinically relevant orthotopic cancer model, and has identified stathmin as an important contributor of cell invasion and metastasis in neuroblastoma.
The cytoskeleton as a therapeutic target in childhood acute leukemia: Obstacles and opportunities
Publisher: Bentham Science Publishers Ltd.
Date: 06-2007
DOI: 10.2174/138945007780830836
Abstract: Antimitotic agents that interfere with the tubulin/microtubule system are important in the treatment of a range of cancers. Natural product tubulin-binding agents such as the Vinca alkaloids have proven highly effective in the treatment of leukemia. Improved understanding of the mechanisms of action of these and related drugs has led to the identification of distinct binding sites on tubulin that cause inhibition of spindle microtubule dynamics, mitotic arrest and cell death. Despite the efficacy of these agents, treatment failure caused by the emergence of drug resistant leukemic cells is a significant clinical problem. Alterations in the cellular target of tubulin-binding agents have been strongly implicated in resistance to these agents. This review will focus on the microtubule cytoskeleton and its role in drug resistance in leukemia. The identification of novel protein pathways involved in drug response and the development of new drugs targeted against microtubules, offers opportunities to treat resistant disease, improve outcome and potentially reduce toxicity for leukemia patients.
βIII-Tubulin Gene Regulation in Health and Disease.
Publisher: Frontiers Media SA
Date: 28-04-2022
DOI: 10.3389/FCELL.2022.851542
Abstract: Microtubule proteins form a dynamic component of the cytoskeleton, and play key roles in cellular processes, such as vesicular transport, cell motility and mitosis. Expression of microtubule proteins are often dysregulated in cancer. In particular, the microtubule protein βIII-tubulin, encoded by the TUBB3 gene, is aberrantly expressed in a range of epithelial tumours and is associated with drug resistance and aggressive disease. In normal cells, TUBB3 expression is tightly restricted, and is found almost exclusively in neuronal and testicular tissues. Understanding the mechanisms that control TUBB3 expression, both in cancer, mature and developing tissues will help to unravel the basic biology of the protein, its role in cancer, and may ultimately lead to the development of new therapeutic approaches to target this protein. This review is devoted to the transcriptional and posttranscriptional regulation of TUBB3 in normal and cancerous tissue.
Evidence that the MYCN oncogene regulates MRP gene expression in neuroblastoma
Publisher: Elsevier BV
Date: 10-1997
DOI: 10.1016/S0959-8049(97)00284-0
Abstract: We have recently shown that expression of the multidrug resistance-associated protein (MRP) gene is a powerful prognostic indicator in childhood neuroblastoma and have suggested that the MYCN oncogene may regulate MRP gene expression. To address this hypothesis, we have examined the relationship between MYCN and MRP gene expression in neuroblastoma tumours and cell lines. MYCN and MRP gene expression were highly correlated in 60 primary untreated tumours both with (P = 0.01) and without MYCN gene lification (P < 0.0001). Like MRP, high MYCN gene expression was significantly associated with reduced survival, both in the overall study population and in older children without MYCN gene lification (relative hazards = 13.33 and 19.61, respectively). Inhibition of MYCN, through the introduction of MYCN antisense RNA constructs into human neuroblastoma cells in vitro, resulted in decreased MRP gene expression, determined both by RNA-PCR and Western analysis. The data are consistent with MYCN influencing neuroblastoma outcome by regulating MRP gene expression.
Novel functional cisplatin carrier based on carbon nanotubes–quercetin nanohybrid induces synergistic anticancer activity against neuroblastoma in vitro
Publisher: Royal Society of Chemistry (RSC)
Date: 07-2014
DOI: 10.1039/C4RA03331K
The cyclin-dependent kinase inhibitor, p21 WAF1 , promotes angiogenesis by repressing gene transcription of thioredoxin-binding protein 2 in cancer cells
Publisher: Oxford University Press (OUP)
Date: 22-09-2009
Abstract: The cyclin-dependent kinase inhibitor, p21(WAF1), induces cell-cycle arrest and can act as a tumor suppressor. However, increasing evidence indicates that p21(WAF1) can also increase resistance to some anticancer therapies and thus promote tumor growth. The mechanisms explaining this paradox have not been explained. We found that conditioned media from MCF-7 breast cancer cells transfected with a p21(WAF1)-specific small interfering RNA (siRNA) significantly reduced endothelial cell migration, invasion and vascular sprouting. Liquid chromatography/mass spectrometry analysis of the conditioned media revealed that p21(WAF1) knockdown significantly reduced secretion of thioredoxin (Trx), a redox protein known to promote tumor angiogenesis. p21(WAF1) knockdown decreased Trx enzymatic activity in cancer cells, by effects on the expression levels of intracellular thioredoxin-binding protein 2 (TBP2), known to bind and inactivate Trx. Consistent with these findings, media from cancer cells transfected with TBP2 siRNA promoted endothelial cell invasion and blocked the anti-angiogenic effect of p21(WAF1) siRNA. Addition of Trx siRNA blocked the pro-angiogenic effects of TBP2 siRNA. Chromatin immunoprecipitation assays showed p21(WAF1) bound TBP2 gene promoter. Taken together, our data suggests that p21(WAF1) can induce Trx secretion and angiogenesis in cancer cells, by direct transcriptional repression of the TBP2 promoter.
Microtubules and resistance to tubulin-binding agents.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2010
DOI: 10.1038/NRC2803
Abstract: Microtubules are dynamic structures composed of alpha-beta-tubulin heterodimers that are essential in cell ision and are important targets for cancer drugs. Mutations in beta-tubulin that affect microtubule polymer mass and/or drug binding are associated with resistance to tubulin-binding agents such as paclitaxel. The aberrant expression of specific beta-tubulin isotypes, in particular betaIII-tubulin, or of microtubule-regulating proteins is important clinically in tumour aggressiveness and resistance to chemotherapy. In addition, changes in actin regulation can also mediate resistance to tubulin-binding agents. Understanding the molecular mechanisms that mediate resistance to tubulin-binding agents will be vital to improve the efficacy of these agents.
From cells to organoids: The evolution of blood-brain barrier technology for modelling drug delivery in brain cancer
Publisher: Elsevier BV
Date: 05-2023
Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells
Publisher: Informa UK Limited
Date: 04-03-2018
Modeling the Distribution of Diprotic Basic Drugs in Liposomal Systems: Perspectives on Malaria Nanotherapy
Publisher: Frontiers Media SA
Date: 25-09-2019
Dextran-Based Doxorubicin Nanocarriers with Improved Tumor Penetration
Publisher: American Chemical Society (ACS)
Date: 18-12-2013
DOI: 10.1021/BM401526D
Abstract: Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of ∼300 nM against two-dimensional (2D) SK-N-BE(2) monolayers. Confocal imaging showed that the ald-dex-dox nanocarriers were rapidly internalized by SK-N-BE(2) cells. Fluorescence lifetime imaging microscopy (FLIM) analysis indicated that ald-dex-dox particles were internalized as intact complexes with the majority of the doxorubicin released from the particle four hours post uptake. Accumulation of the ald-dex-dox particles was significantly enhanced by ∼30% in the absence of glucose indicating a role for glucose and its receptors in their endocytosis. However, inhibition of clathrin dependent and independent endocytosis and macropinocytosis as well as membrane cholesterol depletion had no effect on ald-dex-dox particle accumulation. In three-dimensional (3D) SK-N-BE(2) tumor spheroids, which more closely resemble a solid tumor, the ald-dex-dox nanoparticles showed a significant improvement in efficacy over free doxorubicin, as evidenced by decreased spheroid outgrowth. Drug penetration studies in 3D demonstrated the ability of the ald-dex-dox nanocarriers to fully penetrate into a SK-N-BE(2) tumor spheroids, while doxorubicin only penetrates to a maximum distance of 50 μM. The ald-dex-dox nanocarriers represent a promising therapeutic delivery system for the treatment of solid tumors due to their unique enhanced penetration ability combined with their improved efficacy over the parent drug in 3D.
A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo
Publisher: American Chemical Society (ACS)
Date: 28-06-2016
DOI: 10.1021/ACS.BIOMAC.6B00185
Abstract: Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA) side-arms and varied amounts of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). We showed that star-POEGMA polymers could readily self-assemble with siRNA to form nanoparticles. The star-POEGMA polymers were nontoxic to normal cells and delivered siRNA with high efficiency to pancreatic cancer cells to silence a gene (TUBB3/βIII-tubulin) which is currently undruggable using chemical agents, and is involved in regulating tumor growth and metastases. Notably, systemic administration of star-POEGMA-siRNA resulted in high accumulation of siRNA to orthotopic pancreatic tumors in mice and silenced βIII-tubulin expression by 80% at the gene and protein levels in pancreatic tumors. Together, these novel findings provide strong rationale for the use of star-POEGMA polymers as delivery vehicles for siRNA to pancreatic tumors.
Growth inhibitory retinoid effects after recruitment of retinoid X receptor β to the retinoic acid receptor β promoter
Publisher: Wiley
Date: 15-05-2003
DOI: 10.1002/IJC.11153
Abstract: Nuclear retinoid receptors mediate retinoid effects through tissue-specific, ligand-receptor interactions and subsequent transcriptional regulation of secondary target genes. Retinoic acid receptor beta (RARbeta) is itself a retinoid target gene with a retinoic acid response element (betaRARE) in the 5' untranslated region of the RARbeta2 gene. Altered transcriptional regulation of RARbeta may play a role in human carcinogenesis and the retinoid-responsiveness of malignant cells. Here we used retinoid X receptor-specific antibodies in electrophoretic mobility shift assays to show that the retinoid X receptor beta (RXRbeta) protein was recruited to the betaRARE, after retinoid treatment of retinoid-sensitive neuroblastoma (NB), lung and breast cancer cell lines, but not retinoid-resistant lung and breast cancer cell lines. RXRbeta selectively enhanced retinoid-induced transcriptional activation of the betaRARE. Stable overexpression of RXRalpha and RXRbeta in NB cells resulted in marked growth inhibition and cell death, which increased after retinoid treatment. However, only proteins from the RXRbeta transfectants exhibited specific RXRbeta binding to the betaRARE in vitro and in vivo, enhanced histone acetylation and increased endogenous RARbeta expression. These data indicate that recruitment of RXRbeta to the betaRARE, and consequent induction of endogenous RARbeta expression, is an important component in the retinoid anticancer signal. RXRalpha may also participate in the retinoid signal, but through mechanisms that do not involve RARbeta.
miR-99b-5p, miR-380-3p, and miR-485-3p are novel chemosensitizing miRNAs in high-risk neuroblastoma
Publisher: Elsevier BV
Date: 03-2022
Thymosin‐β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma
Publisher: Wiley
Date: 29-04-2015
Spatial-temporal analysis of nanoparticles in live tumor spheroids impacted by cell origin and density
Publisher: Cold Spring Harbor Laboratory
Date: 28-10-2021
DOI: 10.1101/2021.10.26.465839
Abstract: Nanoparticles hold great preclinical promise in cancer therapy but continue to suffer attrition through clinical trials. Advanced, three dimensional (3D) cellular models such as tumor spheroids can recapitulate elements of the tumor environment and are considered the superior model to evaluate nanoparticle designs. However, there is an important need to better understand nanoparticle penetration kinetics and determine how different cell characteristics may influence this nanoparticle uptake. A key challenge with current approaches for measuring nanoparticle accumulation in spheroids is that they are often static, losing spatial and temporal information which may be necessary for effective nanoparticle evaluation in 3D cell models. To overcome this challenge, we developed an analysis platform, termed the Determination of Nanoparticle Uptake in Tumor Spheroids (DONUTS), which retains spatial and temporal information during quantification, enabling evaluation of nanoparticle uptake in 3D tumor spheroids. Outperforming linear profiling methods, DONUTS was able to measure silica nanoparticle uptake to 10 µm accuracy in both isotropic and irregularly shaped cancer cell spheroids. This was then extended to determine penetration kinetics, first by a forward-in-time, center-in-space model, and then by mathematical modelling, which enabled the direct evaluation of nanoparticle penetration kinetics in different spheroid models. Nanoparticle uptake was shown to inversely relate to particle size and varied depending on the cell type, cell stiffness and density of the spheroid model. The automated analysis method we have developed can be applied to live spheroids in situ , for the advanced evaluation of nanoparticles as delivery agents in cancer therapy.
Assessment of Cholesterol-Derived Ionic Copolymers as Potential Vectors for Gene Delivery
Publisher: American Chemical Society (ACS)
Date: 30-10-2013
DOI: 10.1021/BM4013088
Abstract: A library of cholesterol-derived ionic copolymers were previously synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization as 'smart' gene delivery vehicles that hold erse surface charges. Polyplex systems formed with anionic poly(methacrylic acid-co-cholesteryl methacrylate) (P(MAA-co-CMA)) and cationic poly(dimethylamino ethyl methacrylate-co-cholesteryl methacrylate) (Q-P(DMAEMA-co-CMA)) copolymer series were evaluated for their therapeutic efficiency. Cell viability assays, conducted on SHEP, HepG2, H460, and MRC5 cell lines, revealed that alterations in the copolymer composition (CMA mol %) affected the cytotoxicity profile. Increasing the number of cholesterol moieties in Q-P(DMAEMA-co-CMA) copolymers reduced the overall toxicity (in H460 and HepG2 cells) while P(MAA-co-CMA) series displayed no significant toxicity regardless of the CMA content. Agarose gel electrophoresis was employed to investigate the formation of stable polyplexes and determine their complete conjugation ratios. P(MAA-co-CMA) copolymer series were conjugated to DNA through a cationic linker, oligolysine, while Q-P(DMAEMA-co-CMA)-siRNA complexes were readily formed via electrostatic interactions at conjugation ratios beginning from 6:1:1 (oligolysine-P(MAA-co-CMA)-DNA) and 20:1 (Q-P(DMAEMA-co-CMA)-siRNA), respectively. The hydrodynamic diameter, ζ potential and complex stability of the polyplexes were evaluated in accordance to complexation ratios and copolymer composition by dynamic light scattering (DLS). The therapeutic efficiency of the conjugates was assessed in SHEP cells via transfection and imaging assays using RT-qPCR, Western blotting, flow cytometry, and confocal microscopy. DNA transfection studies revealed P(MAA-co-CMA)-oligolysine-DNA ternary complexes to be ineffective transfection vehicles that mostly adhere to the cell surface as opposed to internalizing and partaking in endosomal disrupting activity. The transfection efficiency of Q-P(DMAEMA-co-CMA)-GFP siRNA complexes were found to be polymer composition and N/P ratio dependent, with Q-2% CMA-GFP siRNA polyplexes at N/P ratio 20:1 showing the highest gene suppression in GFP expressing SHEP cells. Cellular internalization studies suggested that Q-P(DMAEMA-co-CMA)-siRNA conjugates efficiently escaped the endolysosomal pathway and released siRNA into the cytoplasm. The gene delivery profile, reported herein, illuminates the positive and negative attributes of each therapeutic design and strongly suggests Q-P(DMAEMA-co-CMA)-siRNA particles are extremely promising candidates for in vivo applications of siRNA therapy.
Thiol-reactive star polymers functionalized with short ethoxy-containing moieties exhibit enhanced uptake in acute lymphoblastic leukemia cells
Publisher: Informa UK Limited
Date: 12-2019
DOI: 10.2147/IJN.S220326
A Role for Altered Microtubule Polymer Levels in Vincristine Resistance of Childhood Acute Lymphoblastic Leukemia Xenografts
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 06-11-2007
Abstract: The microtubule-depolymerizing drug, vincristine, is effective in the treatment of acute lymphoblastic leukemia (ALL). Although vincristine resistance mechanisms have been extensively characterized in cell lines, their clinical relevance is poorly understood. The aim of the current study was to define clinically relevant mechanisms of vincristine resistance in a panel of childhood ALL xenografts established in immune-deficient (nonobese diabetic/severe combined immunodeficient) mice. We also studied two independent xenograft sublines that were selected by in vivo vincristine exposure. In vitro vincristine sensitivity determined by a stromal coculture, murine bone marrow stromal cell line (MS-5), assay, but not methyl-thiazolyl-tetrazolium metabolic activity assay, significantly correlated (P = 0.05) with the length of the patients' first remission. Investigations into mechanisms of resistance revealed no association with steady-state vincristine accumulation or increased activity and/or expression of ATP-binding cassette transporters, although increased intracellular levels of polymerized tubulin significantly correlated with resistance (r = 0.85 P = 0.0019). Two xenograft sublines selected by in vivo vincristine exposure exhibited a 2-fold increase in polymerized tubulin levels compared with the parental subline (P < 0.05), reflecting their in vivo vincristine resistance. In this study, a vincristine-resistant xenograft with high levels of polymerized tubulin was relatively sensitive to the microtubule-polymerizing drug paclitaxel. These results indicate that the balance between polymerized and nonpolymerized tubulin may be an important determinant of response to Vinca alkaloid-based chemotherapy regimens in childhood ALL.
B-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma
Publisher: Springer Science and Business Media LLC
Date: 21-05-2013
DOI: 10.1038/BJC.2013.205
LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs
Publisher: Springer Science and Business Media LLC
Date: 02-11-2010
DOI: 10.1038/ONC.2009.367
Abstract: LIM-kinase 2 (LIMK2) belongs to the LIMK family of proteins, which comprises LIMK1 and LIMK2. Both proteins regulate actin polymerization through phosphorylation and inactivation of the actin depolymerizing factor cofilin. In this study, we show that the level of LIMK2 protein is increased in neuroblastoma, BE(2)-C cells, selected for resistance to microtubule-destabilizing agents, vincristine and colchicine. However, the level of phosphorylated LIMK1 and LIMK2 was similar in the resistant and parental BE(2)-C cells. In contrast, the level of phospho-cofilin was greatly increased in the drug-resistant cells. Downregulation of LIMK2 expression increases sensitivity of neuroblastoma SH-EP cells to vincristine and vinblastine but not to microtubule-stabilizing agents, while it's overexpression increased its resistance to vincristine. Its vincristine-induced mitotic arrest was moderately inhibited in the LIMK2 knockdown cells, suggesting that the increased drug sensitivity is through an alternative mechanism other then mitotic arrest and apoptosis. Moreover, downregulation of LIMK2 expression induces formation of abnormal mitotic spindles, an effect enhanced in the presence of microtubule-destabilizing agents. LIMK2 is important for normal mitotic spindle formation and altered LIMK2 expression mediates sensitivity to microtubule destabilizing agents. These findings suggest that inhibition of LIMK2 activity may be used for the treatment of tumors resistant to microtubule-destabilizing drugs.
In vivo [64Cu]CuCl2 PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
Publisher: Ivyspring International Publisher
Date: 2018
DOI: 10.7150/THNO.29840
Microtubules, drug resistance, and tumorigenesis
Publisher: Humana Press
Date: 2012
A potent targeted cancer nanotherapeutic
Publisher: Springer Science and Business Media LLC
Date: 05-04-2019
Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats
Publisher: Wiley
Date: 21-03-2019
DOI: 10.1002/JOR.24262
Abstract: Stress fractures (SFx) result from repetitive cyclical loading of bone. They are frequent athletic injuries and underlie atypical femoral fractures following long-term bisphosphonate (BP) therapy. We investigated the effect of a single PTH injection on the healing of SFx in the rat ulna. SFx was induced in 120 female Wistar rats (300 ± 15 g) during a single loading session. A single PTH (8 µg.100g
Functionalizing Biodegradable Dextran Scaffolds Using Living Radical Polymerization: New Versatile Nanoparticles for the Delivery of Therapeutic Molecules
Publisher: American Chemical Society (ACS)
Date: 18-10-2012
DOI: 10.1021/MP300144Y
Abstract: Conferring biodegradability to nanoparticles is vitally important when nanomedicine applications are being targeted, as this prevents potential problems with bioaccumulation of byproducts after delivery. In this work, dextran has been modified (and rendered hydrophobic) by partial acetalation. A solid state NMR method was first developed to fully characterize the acetalated polymers. In a subsequent synthetic step, RAFT functionality was attached via residual unmodified hydroxyl groups. The RAFT groups were then used in a living free radical polymerization reaction to control the growth of hydrophilic PEG-methacrylate chains, thereby generating hiphilic comblike polymers. The hiphilic polymers were then self-assembled in water to form various morphologies, including small vesicles, wormlike rods, and micellar structures, with PEG at the periphery acting as a nonfouling biocompatible polymer layer. The acetalated dextran nanoparticles were designed for potential doxorubicin (DOX) delivery application based on the premise that in the cell compartments (endosome, lysozome) the acetalated dextran would hydrolyze, destroying the nanoparticle structure, releasing the encapsulated DOX. In-vitro studies confirmed minimal cytotoxicity of the (unloaded) nanoparticles, even after 3 days, proving that the hydrolysis products from the acetal groups (methanol and acetone) had no observable cytotoxic effect. An intriguing initial result is reported that in vitro studies of DOX-loaded dextran-nanoparticles (compared to free DOX) revealed an increased differential toxicity toward a cancer cell line when compared to a normal cell line. Efficient accumulation of DOX in a human neuroblastoma cell line (SY-5Y) was confirmed by both confocal microscopy and flow cytometry measurements. Furthermore, the time dependent release of DOX was monitored using fluorescence lifetime imaging microscopy (FLIM) in SY-5Y live cells. FLIM revealed bimodal lifetime distributions, showing the accumulation of both DOX-loaded dextran-nanoparticles and subsequent release of DOX in the living cells. From FLIM data analysis, the amount of DOX released in SY-5Y cells was found to increase from 35% to 55% when the incubation time increased from 3 h to 24 h.
Doxorubicin conjugated, crosslinked, PEGylated particles prepared via one-pot thiol-ene modification of a homopolymer scaffold: synthesis and in vitro evaluation
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0PY00256A
High temporal resolution RNA-seq time course data reveals widespread synchronous activation between mammalian lncRNAs and neighboring protein-coding genes
Publisher: Cold Spring Harbor Laboratory
Date: 27-06-2022
Abstract: The advent of massively parallel sequencing revealed extensive transcription beyond protein-coding genes, identifying tens of thousands of long noncoding RNAs (lncRNAs). Selected functional ex les raised the possibility that lncRNAs, as a class, may maintain broad regulatory roles. Expression of lncRNAs is strongly linked with adjacent protein-coding gene expression, suggesting potential cis -regulatory functions. A more detailed understanding of these regulatory roles may be obtained through careful examination of the precise timing of lncRNA expression relative to adjacent protein-coding genes. Despite the ersity of reported lncRNA regulatory mechanisms, where causal cis -regulatory relationships exist, lncRNA transcription is expected to precede changes in target gene expression. Using a high temporal resolution RNA-seq time course, we profiled the expression dynamics of several thousand lncRNAs and protein-coding genes in synchronized, transitioning human cells. Our findings reveal that lncRNAs are expressed synchronously with adjacent protein-coding genes. Analysis of lipopolysaccharide-activated mouse dendritic cells revealed the same temporal relationship observed in transitioning human cells. Our findings suggest broad-scale cis -regulatory roles for lncRNAs are not common. The strong association between lncRNAs and adjacent genes may instead indicate an origin as transcriptional by-products from active protein-coding gene promoters and enhancers.
Efficient delivery of Temozolomide using ultrasmall large-pore silica nanoparticles for glioblastoma.
Publisher: Elsevier BV
Date: 05-2023
The RhoGAP protein ARHGAP18/SENEX localizes to microtubules and regulates their stability in endothelial cells
Publisher: American Society for Cell Biology (ASCB)
Date: 15-04-2017
Abstract: RhoGTPases are important regulators of the cell cytoskeleton, controlling cell shape, migration and proliferation. Previously we showed that ARHGAP18 in endothelial cells is important in cell junctions. Here we show, using structured illumination microscopy (SIM), ground-state depletion (GSD), and total internal reflection fluorescence microscopy (TIRF) that a proportion of ARHGAP18 localizes to microtubules in endothelial cells, as well as in nonendothelial cells, an association confirmed biochemically. In endothelial cells, some ARHGAP18 puncta also colocalized to Weibel–Palade bodies on the microtubules. Depletion of ARHGAP18 by small interfering RNA or analysis of endothelial cells isolated from ARHGAP18-knockout mice showed microtubule destabilization, as evidenced by altered morphology and decreased acetylated α-tubulin and glu-tubulin. The destabilization was rescued by inhibition of ROCK and histone deacetylase 6 but not by a GAP-mutant form of ARHGAP18. Depletion of ARHGAP18 resulted in a failure to secrete endothelin-1 and a reduction in neutrophil transmigration, both known to be microtubule dependent. Thrombin, a critical regulator of the Rho-mediated barrier function of endothelial cells through microtubule destabilization, enhanced the plasma membrane–bound fraction of ARHGAP18. Thus, in endothelial cells, ARHGAP18 may act as a significant regulator of vascular homeostasis.
Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma
Publisher: MDPI AG
Date: 13-03-2021
Abstract: Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.
Figure S2 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426437.V1
Abstract: Effect of copper levels on PD-L1 expression and interferon stimulation in cancer cells
Water Soluble Antioxidant Dextran–Quercetin Conjugate with Potential Anticancer Properties
Publisher: Wiley
Date: 07-02-2018
Abstract: Quercetin, a naturally occurring potent antioxidant, is limited in therapeutic use, owing to its poor water solubility and stability. Herein, a method of conjugating quercetin to an aldehyde functionalized dextran via an HCl catalyzed condensation reaction to yield a water soluble quercetin functionalized polymer is reported. The prepared conjugate is characterized by
Proteome Analysis of Vinca Alkaloid Response and Resistance in Acute Lymphoblastic Leukemia Reveals Novel Cytoskeletal Alterations
Publisher: Elsevier BV
Date: 11-2003
Telephone-Delivered Interventions for Physical Activity and Dietary Behavior Change
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.AMEPRE.2011.08.025
Abstract: Telephone-delivered interventions targeting physical activity and dietary change have potential for broad population reach and thus have a role to play in addressing increasing rates of lifestyle-related chronic diseases. The purpose of this systematic review is to update the evidence for their potential to inform translation, including effectiveness in promoting maintenance, reporting on implementation, and costs. A structured search of PubMed, MEDLINE, and PsycINFO (January 2006 to April 2010) was conducted. Included studies reported on physical activity and/or dietary change in adults, delivered at least 50% of intervention contacts by telephone, and included a control group (except in dissemination studies). Detailed information on study design, intervention features, and behavioral outcomes was extracted, tabulated, and summarized. Twenty-five studies (27 comparisons) were included: 16 for physical activity, two for diet, and seven for combined interventions. Twenty of 27 comparisons found evidence for initiation of behavior change (14 of 17 comparisons for physical activity two of two for diet four of eight for combined interventions). Ten of 25 studies evaluated post-intervention maintenance of change, with three reporting that maintenance was achieved for at least 50% of outcomes. Dissemination studies were rare (n=3), as were dose-response (n=2) and cost-effectiveness analyses (n=2). Given the strength of evidence for telephone-delivered physical activity and dietary change interventions, greater emphasis on dissemination studies is warranted.
Figure S4 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426431.V1
Abstract: TEPA increases tumor-infiltrating immune cells in Th-MYCN mice
The use of star polymer nanoparticles for the delivery of siRNA to mouse orthotopic pancreatic tumor models
Publisher: Springer New York
Date: 2019
DOI: 10.1007/978-1-4939-9220-1_23
Abstract: Pancreatic cancer is a lethal malignancy which is refractory to most chemotherapy drugs. Recent landmark studies have shed new light on the complex genetic heterogeneity of pancreatic cancer and provide an opportunity to utilize "precision-based medicines" to target genes based on the genetic profile of an in idual's tumor to increase the efficiency of chemotherapy and decrease tumor growth and metastases. Gene-silencing drugs in the form of short-interfering RNA (siRNA) have the potential to play an important role in precision medicine for pancreatic cancer by silencing the expression of genes including those considered difficult to inhibit (undruggable) using chemical agents. However, before siRNA can reach its clinical potential a delivery vehicle is needed to carry siRNA across the cell membrane and into the cytoplasm of the cell. Herein, we detail the methods required to use star polymer nanoparticles to deliver siRNA to pancreatic tumors in an orthotopic pancreatic cancer mouse model to silence the expression of an "undruggable" gene (βIII-tubulin) that regulates pancreatic cancer growth and chemosensitivity.
Metronomic chemotherapy: new rationale for new directions
Publisher: Springer Science and Business Media LLC
Date: 08-06-2010
DOI: 10.1038/NRCLINONC.2010.82
Abstract: Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. The key involvement of angiogenesis in tumor growth and metastasis has started to redefine chemotherapy and new protocols have emerged. Metronomic chemotherapy, which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. The potential of metronomic chemotherapy was revealed in animal models a decade ago and the efficacy of this approach has been confirmed in the clinic. In the past 5 years, multiple clinical trials have investigated the safety and efficacy of metronomic chemotherapy in a variety of human cancers. While the results have been variable, clinical studies have shown that these new treatment protocols represent an interesting alternative for either primary systemic therapy or maintenance therapy. We review the latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients. Accumulating evidence suggests that the efficacy of such treatment may not only rely on anti-angiogenic activity. Potential new mechanisms of action, such as restoration of anticancer immune response and induction of tumor dormancy are discussed. Finally, we highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy.
TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells
Publisher: Springer Science and Business Media LLC
Date: 23-08-2010
DOI: 10.1038/ONC.2010.340
When polymers meet carbon nanostructures: expanding horizons in cancer therapy
Publisher: Future Science Ltd
Date: 08-2019
Abstract: The development of hybrid materials, which combine inorganic with organic materials, is receiving increasing attention by researchers. As a consequence of carbon nanostructures high chemical versatility, they exhibit enormous potential for new highly engineered multifunctional nanotherapeutic agents for cancer therapy. Whereas many groups are working on drug delivery systems for chemotherapy, the use of carbon nanohybrids for radiotherapy is rarely applied. Thus, nanotechnology offers a wide range of solutions to overcome the current obstacles of conventional chemo- and/or radiotherapies. Within this review, the structure and properties of carbon nanostructures (carbon nanotubes, nanographene oxide) functionalized preferentially with different types of polymers (synthetic, natural) are discussed. In short, synthesis approaches, toxicity investigations and anticancer efficacy of different carbon nanohybrids are described.
Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment
Publisher: Impact Journals, LLC
Date: 17-10-2011
Graphene Oxide - Gelatin Nanohybrids as Functional Tools for Enhanced Carboplatin Activity in Neuroblastoma Cells
Publisher: Springer Science and Business Media LLC
Date: 24-12-2014
DOI: 10.1007/S11095-014-1604-Z
Abstract: Preparation of Nanographene oxide (NGO) - Gelatin hybrids for efficient treatment of Neuroblastoma. Nanohybrids were prepared via non-covalent interactions. Spectroscopic tools have been used to discriminate the chemical states of NGO prior and after gelatin coating, with UV visible spectroscopy revealing the maximum binding capacity of gelatin to NGO. Raman and X-ray photoelectron spectroscopy (XPS) demonstrated NGO and Gelatin_NGO nanohybrids through a new chemical environments produced after noncovalent interaction. Microscopic analyses, atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to estimate the thickness of s les and the lateral width in the nanoscale, respectively. The cell viability assay validated Gelatin_NGO nanohybrids as a useful nanocarrier for Carboplatin (CP) release and delivery, without obvious signs of toxicity. The nano-sized NGO (200 nm and 300 nm) did not enable CP to kill the cancer cells efficiently, whilst the CP loaded Gel_NGO 100 nm resulted in a synergistic activity through increasing the local concentration of CP inside the cancer cells. The nanohybrids provoked high stability and dispersibility in physiological media, as well as enhanced the anticancer activity of the chemotherapy agent Carboplatin (CP) in human neuroblastoma cells.
Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.130872
Abstract: Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor–AB and 5-Azacytidine into multipotent stem cells with stromal cell characteristics. To generate a product that is amenable for therapeutic application, we have modified and optimised culture conditions to reprogram human adipocytes into induced multipotent stem cells (iMS) and expand them in vitro . The basal transcriptomes of adipocyte-derived iMS cells and matched adipose-tissue-derived mesenchymal stem cells were remarkably similar. However, there were distinct changes in histone modifications and CpG methylation at cis- regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to new muscle, bone, cartilage and blood vessels with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibres without ectopic tissue formation. Taken together, human adipocyte derived iMS cells regenerate tissues in a context dependent manner without ectopic or neoplastic growth.
Potential applications of nanotechnology for the diagnosis and treatment of pancreatic cancer
Publisher: Frontiers Media SA
Date: 2014
Tubulin-targeted drug action: functional significance of class ii and class IVb beta-tubulin in vinca alkaloid sensitivity.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2008
DOI: 10.1158/0008-5472.CAN-08-1501
Abstract: Aberrant expression of β-tubulin isotypes is frequently described in tumor tissues and tubulin-binding agent (TBA)–resistant cell lines. There is limited understanding of the role of specific β-tubulin isotypes in cellular sensitivity to TBAs, and to gain insights into the functional role of βII- and βIVb-tubulin, we examined these isotypes in lung cancer cell lines NCI-H460 (H460) and Calu-6. Drug-treated clonogenic assays revealed that small interfering RNA–mediated knockdown of either βII- or βIVb-tubulin hypersensitized the lung cancer cell lines to Vinca alkaloids, with the effects more pronounced following βIVb-tubulin knockdown. In contrast, there was no change in paclitaxel sensitivity following knockdown of either isotype. Cell cycle analysis revealed a greater propensity for the βII- and βIVb-tubulin knockdown cells to undergo G2-M cell cycle block following 5 nmol/L vincristine treatment, with the βIVb knockdown cells being more sensitive than the βII-tubulin knockdown cells compared with control. In contrast to βII-tubulin knockdown, βIVb-tubulin knockdown cells showed a significant increase in the sub-G1 population (cell death) following treatment with both 5 and 40 nmol/L of vincristine compared with controls. Importantly, βIVb-tubulin knockdown in H460 cells caused a significant dose-dependent increase in Annexin V staining in response to vincristine but not paclitaxel. Therefore, increased sensitivity to induction of apoptosis is one mechanism underlying the Vinca alkaloid hypersensitivity. This study provides direct evidence that βII- or βIVb-tubulins have functionally distinct roles and expression of these isotypes may serve as strong predictors of Vinca alkaloid response and resistance. [Cancer Res 2008 (23):9817–24]
βIII-Tubulin Structural Domains Regulate Mitochondrial Network Architecture in an Isotype-Specific Manner.
Publisher: MDPI AG
Date: 23-02-2022
Abstract: βIII-tubulin is a neuronal microtubule protein that is aberrantly expressed in epithelial cancers. The microtubule network is implicated in regulating the architecture and dynamics of the mitochondrial network, although the isotype-specific role for β-tubulin proteins that constitute this microtubule network remains unclear. High-resolution electron microscopy revealed that manipulation of βIII-tubulin expression levels impacts the volume and shape of mitochondria. Analysis of the structural domains of the protein identifies that the C-terminal tail of βIII-tubulin, which distinguishes this protein from other β-tubulin isotypes, significantly contributes to the isotype-specific effects of βIII-tubulin on mitochondrial architecture. Mass spectrometry analysis of protein–protein interactions with β-tubulin isotypes identifies that βIII-tubulin specifically interacts with regulators of mitochondrial dynamics that may mediate these functional effects. Advanced quantitative dynamic lattice light sheet imaging of the mitochondrial network reveals that βIII-tubulin promotes a more dynamic and extended reticular mitochondrial network, and regulates mitochondrial volume. A regulatory role for the βIII-tubulin C-terminal tail in mitochondrial network dynamics and architecture has widespread implications for the maintenance of mitochondrial homeostasis in health and disease.
Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy
Publisher: Ivyspring International Publisher
Date: 2022
DOI: 10.7150/THNO.69682
Specific β-Tubulin Isotypes Can Functionally Enhance or Diminish Epothilone B Sensitivity in Non-Small Cell Lung Cancer Cells
Publisher: Public Library of Science (PLoS)
Date: 29-06-2011
Tuning the Mechanical Properties of Multiarm RAFT-Based Block Copolyelectrolyte Hydrogels via Ionic Cross-Linking for 3D Cell Cultures
Publisher: American Chemical Society (ACS)
Date: 14-12-2023
Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-01-2021
Abstract: Human adipocytes are a source of tissue-regenerative multipotent stem cells.
Discovering novel strategies for antimicrotubule cytotoxic therapy
Publisher: Elsevier BV
Date: 07-2006
Two classes of single-stranded regions evident in deproteinized preparations of replicating DNA isolated from mammalian cells.
Publisher: Elsevier BV
Date: 02-1991
DOI: 10.1016/0014-4827(91)90087-B
Abstract: In DNA isolated from proliferating human lymphoblastoid CCRF-CEM cells which had been pulse-labeled by exposure to [3H]thymidine for periods from 30 s to 10 min, single-stranded regions were analyzed by caffeine-gradient elution from benzoylated DEAE-cellulose. Two classes of structural defect were evident. Some replicating DNA exhibited single-stranded regions of approximately 200 nucleotides, while most newly incorporated radioactivity was associated with DNA containing single-stranded regions from 900 to approximately 4000 nucleotides. The distribution of thymidine-derived radioactivity did not suggest sequential or preferential labeling of these DNA fractions as the incorporation time was varied. The findings may be correlated with recent proposals regarding the structural basis of eukaryotic DNA replication.
Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration
Publisher: Elsevier BV
Date: 15-06-1990
DOI: 10.1016/0304-3835(90)90102-4
Abstract: A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.
Within-event learning is disrupted by social isolation immediately after compound exposure
Publisher: Elsevier BV
Date: 28-03-2007
DOI: 10.1016/J.BBR.2006.12.017
Abstract: Exposure to banana scented salty water produced a preference for that smell in rats tested under a sodium appetite (experiment 1), and exposure to almond scented sweet water produced avoidance of that smell when rats were tested after developing an aversion to the sweet taste (experiment 2). The consolidation of this within-event learning was disrupted when exposure to the solutions were followed by social isolation. These results duplicate the disruptive effect of social isolation on context learning and raise the possibility that within-event learning like context learning may involve the hippoc al formation.
A photoelectrochemical platform for the capture and release of rare single cells
Publisher: Springer Science and Business Media LLC
Date: 12-06-2018
DOI: 10.1038/S41467-018-04701-Y
Abstract: For many normal and aberrant cell behaviours, it is important to understand the origin of cellular heterogeneity. Although powerful methods for studying cell heterogeneity have emerged, they are more suitable for common rather than rare cells. Exploring the heterogeneity of rare single cells is challenging because these rare cells must be first pre-concentrated and undergo analysis prior to classification and expansion. Here, a versatile capture & release platform consisting of an antibody-modified and electrochemically cleavable semiconducting silicon surface for release of in idual cells of interest is presented. The captured cells can be interrogated microscopically and tested for drug responsiveness prior to release and recovery. The capture & release strategy was applied to identify rare tumour cells from whole blood, monitor the uptake of, and response to, doxorubicin and subsequently select cells for single-cell gene expression based on their response to the doxorubicin.
βIII-Tubulin alters glucose metabolism and stress response signaling to promote cell survival and proliferation in glucose-starved non-small cell lung cancer cells
Publisher: Oxford University Press (OUP)
Date: 04-05-2016
Abstract: Non-small cell lung cancer (NSCLC) survival rates are dismal and high βIII-tubulin expression is associated with chemotherapy drug resistance and tumor aggressiveness in this disease. Mounting evidence supports a role for βIII-tubulin in promoting cell survival in the harsh tumor microenvironment, which is characterized by poor nutrient supply. This study aimed to investigate the role of βIII-tubulin in glucose stress response signaling and the survival and proliferation of NSCLC cells. This study revealed that βIII-tubulin regulates cellular metabolism and glucose stress response signaling in NSCLC cells to promote cell survival and proliferation in glucose starvation. βIII-Tubulin decreases the reliance of cells on glycolytic metabolism, priming them to cope with variable nutrient supply present within the tumor microenvironment. βIII-Tubulin protects cells from endoplasmic reticulum (ER) stress and reduces both basal and glucose starvation-induced autophagy to maintain cell survival and proliferation. βIII-Tubulin enables rapid Akt activation in response to glucose starvation and co-immunoprecipitates with the master regulator of the ER stress response GRP78. Furthermore, suppression of βIII-tubulin delays the association of GRP78 with Akt in response to glucose starvation with the potential to influence Akt activation and ER homeostasis under these conditions. Together these results identify that βIII-tubulin regulates glucose metabolism and alters glucose starvation stress signaling to promote cell proliferation and survival in NSCLC cells. This elucidates a hitherto unknown role for this microtubule protein and provides insight into correlations between high βIII-tubulin expression and poor patient outcome in this disease.
A Covalently Crosslinked Ink for Multimaterials Drop‐on‐Demand 3D Bioprinting of 3D Cell Cultures
Publisher: Wiley
Date: 25-06-2021
Abstract: In vitro 3D cell models have been accepted to better recapitulate aspects of in vivo organ environment than 2D cell culture. Currently, the production of these complex in vitro 3D cell models with multiple cell types and microenvironments remains challenging and prone to human error. Here, a versatile ink comprising a 4‐arm poly(ethylene glycol) (PEG)‐based polymer with distal maleimide derivatives as the main ink component and a bis‐thiol species as the activator that crosslinks the polymer to form the hydrogel in less than a second is reported. The rapid gelation makes the polymer system compatible with 3D bioprinting. The ink is combined with a novel drop‐on‐demand 3D bioprinting platform, designed specifically for producing 3D cell cultures, consisting of eight independently addressable nozzles and high‐throughput printing logic for creating complex 3D cell culture models. The combination of multiple nozzles and fast printing logic enables the rapid preparation of many complex 3D cell cultures comprising multiple hydrogel environments in one structure in a standard 96‐well plate format. The platform's compatibility for biological applications is validated using pancreatic ductal adenocarcinoma cancer (PDAC) and human dermal fibroblast cells with their phenotypic responses controlled by tuning the hydrogel microenvironment.
Synthesis, anti-cancer and anti-inflammatory activity of novel 2-substituted isoflavenes
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.BMC.2014.08.010
Abstract: Fifteen novel 2-substituted isoflavenes were synthesised via nucleophilic addition to isoflavylium salts. Twelve of the newly synthesised isoflavenes, along with the unsubstituted parent isoflavene, were tested in cell viability assays against the SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. While the 2-substituted isoflavenes displayed a range of anti-proliferative activities, in most cases they were less active that the unsubstituted isoflavene (IC50=9.9 μM vs SHEP IC50=33 μM vs MDA-MB-231). However, compound 7f, derived from the reaction between isoflavylium salt 5 and para-methoxyacetophenone, showed improved anti-proliferative activity against breast cancer cells (IC50=7.6 μM). Furthermore, compound 7f, as well as analogues 7a, 7c, 11d and 14, inhibited the production of interleukin-6 in LPS-activated RAW 264.7 cells.
Figure S7 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426422.V1
Abstract: TEPA did not affect tumor growth in an immunocompromised neuroblastoma xenograft model
Using Fluorescence Lifetime Imaging Microscopy to Monitor Theranostic Nanoparticle Uptake and Intracellular Doxorubicin Release
Publisher: American Chemical Society (ACS)
Date: 16-10-2013
DOI: 10.1021/NN404407G
Abstract: We describe the synthesis of iron oxide nanoparticles (IONPs) with excellent colloidal stability in both water and serum, imparted by carefully designed grafted polymer shells. The polymer shells were built with attached aldehyde functionality to enable the reversible attachment of doxorubicin (DOX) via imine bonds, providing a controlled release mechanism for DOX in acidic environments. The IONPs were shown to be readily taken up by cell lines (MCF-7 breast cancer cells and H1299 lung cancer cells), and intracellular release of DOX was proven using in vitro fluorescence lifetime imaging microscopy (FLIM) measurements. Using the fluorescence lifetime difference exhibited by native DOX (~1 ns) compared to conjugated DOX (~4.6 ns), the intracellular release of conjugated DOX was in situ monitored in H1299 and was estimated using phasor plot representation, showing a clear increase of native DOX with time. The results obtained from FLIM were corroborated using confocal microscopy, clearly showing DOX accumulation in the nuclei. The IONPs were also assessed as MRI negative contrast agents. We observed a significant change in the transverse relaxivity properties of the IONPs, going from 220 to 390 mM(-1) s(-1), in the presence or absence of conjugated DOX. This dependence of MRI signal on IONP-DOX/water interactions may be exploited in future theranostic applications. The in vitro studies were then extended to monitor cell uptake of the DOX loaded IONPs (IONP@P(HBA)-b-P(OEGA) + DOX) into two 3D multicellular tumor spheroids (MCS) grown from two independent cell lines (MCF-7 and H1299) using multiphoton excitation microscopy.
Modulating the Selectivity and Stealth Properties of Ellipsoidal Polymersomes through a Multivalent Peptide Ligand Display
Publisher: Wiley
Date: 19-05-2020
Resistance to Tetracycline, a Hydrophilic Antibiotic, Is Mediated by P-Glycoprotein in Human Multidrug-Resistant Cells
Publisher: Elsevier BV
Date: 1993
Abstract: Two multidrug-resistant human leukemic CCRF-CEM sublines (CEM/VCR R and CEM/VLB100) were significantly more resistant to tetracycline, a hydrophilic antibiotic, than parental cells (P < 0.001). Verapamil and cyclosporin A completely reversed tetracycline resistance in CEM/VCR R cells, which also accumulated and retained significantly less [3H]tetracycline than CCRF-CEM cells. Like verapamil, addition of tetracycline to CEM/VCR R cells which had achieved steady-state vincristine levels resulted in augmented vincristine accumulation. [3H]Azidopine photoaffinity labelling of CEM/VCR R membrane proteins was inhibited by tetracycline in a dose-dependent manner. Although drugs associated with the multidrug-resistance phenotype are typically hydrophobic compounds, these data suggest that resistance to tetracycline, despite its hydrophilic nature, is mediated by P-glycoprotein in these cell lines.
Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery
Publisher: American Chemical Society (ACS)
Date: 26-07-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00851
Abstract: Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70% however, children are often left with long-term treatment side effects. New therapies that maintain a high cure rate while reducing off-target toxicity are required. We describe for the first time the use of a bacteriophage-peptide display library to identify heptapeptides that bind to medulloblastoma cells. Two heptapeptides that demonstrated high [E1-3 (
A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
Publisher: Springer Science and Business Media LLC
Date: 22-01-2019
Role of pancreatic stellate cells in chemoresistance in pancreatic cancer
Publisher: Frontiers Media SA
Date: 09-04-2014
Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter
Publisher: Cold Spring Harbor Laboratory
Date: 07-04-2020
DOI: 10.1101/2020.04.06.028548
Abstract: 3D in vitro cancer models are important therapeutic and biological discovery tools, yet formation of multicellular spheroids in a throughput and highly controlled manner to achieve robust and statistically relevant data, remains challenging. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of high-throughput printing of 96-well plates of spheroids. 3D-multicellular spheroids are embedded inside a tissue-like matrix with precise control over size and cell number. Application of 3D bioprinting for high-throughput drug screening was demonstrated with doxorubicin. Measurements showed that IC 50 values were sensitive to spheroid size, embedding and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust high-throughput platform to screen biological and therapeutic parameters. In vitro 3D cell cultures serve as more realistic models, compared to 2D cell culture, for understanding erse biology and for drug discovery. Preparing 3D cell cultures with defined parameters is challenging, with significant failure rates when embedding 3D multicellular spheroids into extracellular mimics. Here, we report a new 3D bioprinter we developed in conjunction with bioinks to allow 3D-multicellular spheroids to be produced in a high-throughput manner. High-throughput production of embedded multicellular spheroids allowed entire drug-dose responses to be performed in 96-well plate format with statistically relevant numbers of data points. We have deconvoluted important parameters in drug responses including the impact of spheroid size and embedding in an extracellular matrix mimic on IC 50 values.
Effects of a Novel Long Noncoding RNA, lncUSMycN, on N-Myc Expression and Neuroblastoma Progression
Publisher: Oxford University Press (OUP)
Date: 06-2014
DOI: 10.1093/JNCI/DJU113
Abstract: Patients with neuroblastoma due to the lification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb licon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastoma patients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was co lified with MYCN in 88 of 341 human neuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in human neuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03 NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that lification of long noncoding RNA genes can contribute to tumorigenesis.
Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-05-2023
DOI: 10.1126/SCITRANSLMED.ABM1262
Abstract: High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a “mix-and-match” principle where BsAbs were selected on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and patient-derived s les that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia.
The RNA‐helicase DDX21 upregulates CEP55 expression and promotes neuroblastoma
Publisher: Wiley
Date: 26-02-2021
Acid-cleavable polymeric core–shell particles for delivery of hydrophobic drugs
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.JCONREL.2006.07.025
Abstract: Here we describe the combined use of acid-labile microgel approach and RAFT-mediated seeded dispersion polymerization technique to prepare an acid-cleavable core-shell like polymeric colloidal system for the delivery of hydrophobic drugs at slightly acidic sites. A new bisacrylate acetal crosslinker was copolymerized with n-butyl acrylate (BA) in the presence of a RAFT agent using a dispersion polymerization technique, which yielded crosslinked spherical particles with the size ranging between 150 and 500 nm. The particles were cleaved in a pH-dependent manner similar to the acid-labile hydrolysis behaviour of the crosslinker. In order to mask the hydrophobic surface of the particles, polyethylene glycol acrylate (PEG-A) was grafted onto poly(BA) seed particles via the RAFT agent groups on the particle surface. The acidic-site selective delivery potential of the poly(BA)-g-poly(PEG-A) particles was assessed in-vitro using a lipophilic fluorescent dye as a model hydrophobic drug. Ca. 73% and 34% of the total dye loaded in the particles was found to be released at pH 5.0 and 7.4 in 24 h, respectively. The growth of human neuroblastoma cells was not affected by the incubation with the core-shell particles and their cleavage by-products up to 3 mg/ml concentration. The physicochemical and the functional features support the potential value of the acid-cleavable poly(BA) core-poly(PEG-A) shell particles as carriers for the delivery of hydrophobic drugs at acidic sites.
Delineating the Role of βIV-Tubulins in Pancreatic Cancer: βIVb-Tubulin Inhibition Sensitizes Pancreatic Cancer Cells to Vinca Alkaloids
Publisher: Elsevier BV
Date: 12-2016
Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
Publisher: Frontiers Media SA
Date: 19-07-2022
Abstract: Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia ( MLL / KMT2A ) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A -rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.
Erratum
Publisher: Oxford University Press (OUP)
Date: 29-10-2014
DOI: 10.1093/JNCI/DJU359
Neuronal-associated microtubule proteins class III β-tubulin and MAP2c in neuroblastoma: Role in resistance to microtubule-targeted drugs
Publisher: American Association for Cancer Research (AACR)
Date: 09-2004
DOI: 10.1158/1535-7163.1137.3.9
Abstract: Advanced stage neuroblastoma has a poor clinical outcome and microtubule-destabilizing agents, such as the Vinca alkaloids, are an important component in the treatment of this childhood cancer. Vinca alkaloids bind to β-tubulin on the α/β-tubulin heterodimer and disrupt microtubule dynamics, leading to cell death. To date, studies examining the contribution of microtubules and associated proteins to the efficacy of microtubule-destabilizing agents in neuroblastoma have been limited. In this study, BE(2)-C neuroblastoma cells previously selected for resistance to either vincristine (BE/VCR10) or colchicine (BE/CHCb0.2) were found to display significant decreases in neuronal-specific class III β-tubulin. Interestingly, vincristine-selected cells exhibited increased levels of polymerized tubulin that were not due to α-tubulin and class I, II, or III β-tubulin mutations. Expression levels of the microtubule-depolymerizing protein stathmin were significantly increased in BE/VCR10 cells. In contrast, levels of MAP2a and MAP2b were relatively unaltered. A marked decrease in the neuronal protein, MAP2c, was identified in the vincristine-selected cells and, to a lesser extent, in the colchicine-selected cells. This is the first report describing specific microtubule alterations in neuroblastoma cells resistant to tubulin-targeted agents. The results indicate a need to identify the factors responsible for resistance to tubulin-targeted agents in neuroblastoma so that improved and novel treatment strategies can be developed for this drug refractory disease.
Karyotypic analysis of CCRF-CEM and drug-resistant cell lines with stable and unstable ploidy
Publisher: Elsevier BV
Date: 03-1993
DOI: 10.1016/0165-4608(93)90149-G
Abstract: Karyotypic studies were performed on methotrexate (MTX)- and vincristine (VCR)-resistant cell lines derived from the human T-cell leukemia CCRF-CEM cell line. We noted karyotypic selection and additional chromosome change associated with acquisition of drug-resistance. Furthermore, we observed that both the parental and MTX-resistant sublines, CEM/MTX R1-3, had a tendency to ploidy change. Karyotypic studies of malignant cells have shown that polyploidy is frequently a consequence of a single sporadic event, followed by growth and selection of the polyploid clone [1]. In this study, however, various karyotypic clones were identified with near- and pseudotetraploid karyotypes that appeared to be derived from different near- and pseudodiploid sidelines. Polyploidy was invariably associated with loss of at least two of the four chromosomes 8 whether the pseudodiploid sideline from which it was derived carried one or both chromosomes 8. In contrast, neither polyploid clones nor loss of chromosome 8 was noted in the CEM/VCR R cells.
Integrative analysis of RUNX1 downstream pathways and target genes
Publisher: Springer Science and Business Media LLC
Date: 31-07-2008
Abstract: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or lification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFβ, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ . A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.
An Emerging Role for Tubulin Isotypes in Modulating Cancer Biology and Chemotherapy Resistance
Publisher: MDPI AG
Date: 04-07-2017
DOI: 10.3390/IJMS18071434
Microtubules: a dynamic target in cancer therapy.
Publisher: Wiley
Date: 19-02-2008
DOI: 10.1002/IUB.25
Abstract: The tubulin/microtubule system is an important target for anticancer therapy. Two of the most clinically valuable groups of these agents are the vinca alkaloids and taxanes. In recent years, new tubulin-binding agents have been under preclinical or clinical development. One of these classes of agents, epothilones, has shown great promise in phase III clinical trials. What all these agents share in common, is that they bind to beta-tubulin and disrupt microtubule function during mitosis which in turn leads to mitotic arrest and cell death. In addition, these agents can inhibit angiogenesis. Not withstanding their effectiveness, drug resistance can pose a major clinical problem. This review provides an overview of the mechanisms mediating resistance to tubulin-binding agents related to the cellular target and discusses strategies to overcome this important clinical problem.
Minimum information reporting in bio-nano experimental literature
Publisher: Springer Science and Business Media LLC
Date: 09-2018
The Estrogen-responsive B Box Protein Is a Novel Regulator of the Retinoid Signal
Publisher: Elsevier BV
Date: 2006
The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.CANLET.2008.11.030
Abstract: Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) beta(2) is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARbeta2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARbeta2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARbeta2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (betaRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARbeta2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.
Application of Rapid Fluorescence Lifetime Imaging Microscopy (RapidFLIM) to Examine Dynamics of Nanoparticle Uptake in Live Cells
Publisher: MDPI AG
Date: 12-02-2022
Abstract: A key challenge in nanomedicine stems from the continued need for a systematic understanding of the delivery of nanoparticles in live cells. Complexities in delivery are often influenced by the biophysical characteristics of nanoparticles, where even subtle changes to nanoparticle designs can alter cellular uptake, transport and activity. Close examination of these processes, especially with imaging, offers important insights that can aid in future nanoparticle design or translation. Rapid fluorescence lifetime imaging microscopy (RapidFLIM) is a potentially valuable technology for examining intracellular mechanisms of nanoparticle delivery by directly correlating visual data with changes in the biological environment. To date, applications for this technology in nanoparticle research have not been explored. A PicoQuant RapidFLIM system was used together with commercial silica nanoparticles to follow particle uptake in glioblastoma cells. Importantly, RapidFLIM imaging showed significantly improved image acquisition speeds over traditional FLIM, which enabled the tracking of nanoparticle uptake into subcellular compartments. We determined mean lifetime changes and used this to delineate significant changes in nanoparticle lifetimes ( .39 ns), which showed clustering of these tracks proximal to both extracellular and nuclear membrane boundaries. These findings demonstrate the ability of RapidFLIM to track, localize and quantify changes in single nanoparticle fluorescence lifetimes and highlight RapidFLIM as a valuable tool for multiparameter visualization and analysis of nanoparticle molecular dynamics in live cells.
A high-throughput 3D bioprinted cancer cell migration and invasion model with versatile and broad biological applicability
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2BM00651K
Abstract: A HTP 3D bioprinted cell migration platform that has broad applications across quantitative cell and cancer biology as well as drug screening.
Determination of N-myc gene amplification in neuroblastoma by differential polymerase chain reaction
Publisher: Elsevier BV
Date: 06-1993
Abstract: Determination of N-myc gene lification, a powerful prognostic indicator in the childhood tumour, neuroblastoma, has routinely been performed by Southern analysis. We have developed a differential polymerase chain reaction (PCR) assay, in which the N-myc target gene is co- lified with a control gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Following electrophoresis, a ratio between the two PCR products within a given DNA s le is then determined by densitometry. This assay was applied to DNA isolated from 32 primary neuroblastoma tumours for which the N-myc status had previously been determined by Southern analysis. Following PCR, s les containing a single copy of the N-myc oncogene were clearly distinguishable from s les with N-myc gene lification, based on an N-myc/GAPDH ratio of below or above 1.0, respectively. Linear regression indicated a highly significant relationship (R = 0.94 P < 0.0001) between N-myc copy number (Southern) and N-myc/GAPDH ratio (PCR). Serial dilution of N-myc lified DNA with non- lified control DNA indicated that the PCR assay was sufficiently sensitive to detect two-fold lification. Moreover, such serial dilution allowed determination of N-myc copy number. The assay, which requires only small amounts of tissue and does not utilize 32P-radioactivity, therefore provides a rapid and sensitive alternative to Southern analysis.
A 3D Bioprinter Specifically Designed for the High-Throughput Production of Matrix-Embedded Multicellular Spheroids
Publisher: Elsevier BV
Date: 10-2020
Reply: Comment on 'beta-blockers increase response to chemotherapy via direct anti-tumour and anti-angiogenic mechanisms in neuroblastoma'-β- blockers are potent anti-angiogenic and chemo-sensitising agents, rather than cytotoxic drugs
Publisher: Springer Science and Business Media LLC
Date: 22-08-2013
DOI: 10.1038/BJC.2013.498
Alterations in γ-Actin and Tubulin-Targeted Drug Resistance in Childhood Leukemia
Publisher: Oxford University Press (OUP)
Date: 04-10-2006
DOI: 10.1093/JNCI/DJJ372
Abstract: Proteomic investigations have revealed alterations in cytoskeletal proteins expressed in human acute lymphoblastic leukemia cells that are resistant to microtubule-disrupting agents. We characterized gamma-actin expression in antimicrotubule drug-resistant leukemia and examined the effect of altered gamma-actin in resistance of acute lymphoblastic leukemia to antimicrotubule agents. Two-dimensional polyacrylamide gel electrophoresis and mass spectrometry were used to identify actin proteins in human acute lymphoblastic leukemia cell lines resistant to vinblastine (CCRF-CEM/VLB100 cells) and desoxyepothilone B (CCRF-CEM/dEpoB140 cells). Fluorescence-based cycle sequencing was used to detect gene mutations. Site-directed mutagenesis was used to generate mutant gamma-actin expression plasmids, which were used to transfect mouse NIH/3T3 cells. Clonogenic analysis was used for drug sensitivity studies. A small interfering RNA (siRNA) was used to block gamma-actin gene expression in human neuroblastoma SH-EP cells. Expression of gamma-actin (normalized to that of beta2-microglobulin [beta2M]) in primary leukemia cells obtained from patients at diagnosis (n = 44) and relapse (n = 25) was examined using semiquantitative reverse transcription-polymerase chain reaction. Statistical significance of changes in the ratio of gamma-actin to beta2M expression between diagnosis and relapse s les was determined by two-sided unpaired Student's t tests. We identified novel mutant forms of gamma-actin and the concomitant loss of wild-type gamma-actin in CCRF-CEM/VLB100 cells and CCRF-CEM/dEpoB140 cells. Mouse NIH/3T3 cells that expressed the mutant gamma-actin proteins were more resistant to antimicrotubule agents than cells transfected with empty plasmid. Human neuroblastoma SH-EP cells transfected with gamma-actin siRNA displayed higher relative resistance to paclitaxel (P<.001), vinblastine (P = .04), and epothilone B (P = .045) than mock-transfected cells. No gamma-actin gene mutations were identified in 37 s les of primary leukemia cells (eight from patients at diagnosis, 29 from patients at relapse). Gamma-actin gene expression was lower in acute lymphoblastic leukemia s les collected at clinical relapse (n = 25 mean gamma-actin/beta2M = 0.53) than in s les collected at diagnosis (n = 44 mean gamma-actin/beta2M = 0.68 difference = 0.15, 95% confidence interval [CI] = 0.04 to 0.27, P = .01). These data provide functional and associative clinical evidence of a novel form of drug resistance that involves interactions between gamma-actin and microtubules.
Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 10-2020
DOI: 10.1158/0008-5472.CAN-20-0471
Abstract: These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity.
Proteomic anlaysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia - an in vivo study
Publisher: Wiley
Date: 03-2006
Abstract: Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR-sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2-D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin- and/or tubulin-binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP-G, HSP27, HSP70, TCP-1, and stathmin were associated with in vivo VCR resistance. The actin-regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, gamma-actin, was down-regulated in the VCR-resistant leukemia xenografts in contrast, there was no significant change in beta-actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2-D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer.
βIII-Tubulin: A novel mediator of chemoresistance and metastases in pancreatic cancer
Publisher: Impact Journals, LLC
Date: 10-12-2014
Abstract: Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, β-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of β-tubulins in pancreatic cancer are unknown. We measured the expression of different β-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence βIII-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of βIII-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that βIII-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing βIII-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of βIII-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that βIII-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients.
Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia
Publisher: MDPI AG
Date: 14-10-2021
DOI: 10.3390/PHARMACEUTICS13101681
Abstract: Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered ‘undruggable’ targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8 ) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤ 0.22 along with a % siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells ( % of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML.
Data from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512334.V1
Abstract: Abstract Therapeutic checkpoint antibodies blocking programmed death receptor 1 rogrammed death ligand 1 (PD-L1) signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intratumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the The Cancer Genome Atlas database and tissue microarrays showed strong correlation between the major copper influx transporter copper transporter 1 (CTR-1) and PD-L1 expression across many cancers but not in corresponding normal tissues. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNA sequencing revealed that copper regulates key signaling pathways mediating PD-L1–driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Copper-chelating drugs also significantly increased the number of tumor-infiltrating CD8 sup + /sup T and natural killer cells, slowed tumor growth, and improved mouse survival. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anticancer immunotherapy might be enhanced by pharmacologically reducing intratumor copper levels. Significance: These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity. /
MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors
Publisher: Elsevier BV
Date: 04-1996
DOI: 10.1016/0304-3835(96)04143-2
Abstract: Clinical drug resistance poses a major problem in the successful treatment of ovarian cancer. Two genes, MDR1 and MRP, have been found to play a role in the multidrug resistance phenotype of a number of human tumors. Using a sensitive semiquantitative PCR assay we examined 53 primary untreated ovarian tumors for expression of both MDR1 and MRP genes. Approximately one-third of the tumors expressed MDR1 while all the tumors expressed varying levels of the MRP gene.
Interplay between MycN and c-Myc regulates radioresistance and cancer stem cell phenotype in neuroblastoma upon glutamine deprivation
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/THNO.42602
Figure S5 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426428
Abstract: DC increases tumor-infiltrating immune cells in Th-MYCN mice
Facile synthesis of lactoferrin conjugated ultra small large pore silica nanoparticles for the treatment of glioblastoma
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1NR03553C
Abstract: In this work, we successfully synthesise novel ultra-small (30 nm), large pore (7 nm) silica nanoparticles conjugated with lactoferrin a targeting ligand and demonstrate its utility for improving drug delivery across brain to treat Glioblastoma.
Figure S7 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426422
Abstract: TEPA did not affect tumor growth in an immunocompromised neuroblastoma xenograft model
Targeting βIII-Tubulin in Glioblastoma Multiforme: From Cell Biology and Histopathology to Cancer Therapeutics
Publisher: Bentham Science Publishers Ltd.
Date: 10-2011
DOI: 10.2174/187152011797378760
Abstract: Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults. Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20 years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previously demonstrated increased expression of βIII-tubulin in GBM asserting a link between aberrant expression of this β-tubulin isotype and a disruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignant transformation of a low-grade glioma into GBM. This article reviews βIII-tubulin as a promising target in the experimental treatment of GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in βIII-tubulin-expressing tumor cells, as well as the "double hit" therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by βIII-tubulin silencing. The latest progress regarding the function and potential role of βIII-tubulin in aggressive tumor behavior, cancer stem cells, tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised.
Figure S6 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426425
Abstract: Copper lowering drugs increased NK-mediated cell death in vitro
The role of multidrug resistance-associated protein (MRP) expression in multidrug resistance
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1997
DOI: 10.1097/00001813-199701000-00002
Abstract: Multidrug resistance (MDR) is a major hindrance to the successful treatment of neoplastic disease. The development of resistance to multiple chemotherapeutic drugs is a complex phenomenon which has been described in both tumor cell lines and human cancers. To date, two mechanisms associated with overexpression of membrane glycoproteins that function as energy-dependent efflux pumps to reduce intracellular drug levels have been identified for MDR. The first described was the product of the MDR1 gene, P-glycoprotein. The second mechanism is mediated by overexpression of the multidrug resistance-associated protein (MRP). While these proteins both belong to the ATP-binding cassette superfamily of transporters, they are only distantly related. Despite this low homology, they mediate resistance to a similar range of chemotherapeutic drugs. While P-glycoprotein has been well described in the literature, much less is known about the recently identified MRP. This review gives an overview of the characteristics of MRP at both the phenotypic and genotypic levels, and discusses its possible relevance in drug-refractory cancer.
Anticancer therapy with novel tubulin-interacting drugs
Publisher: Elsevier BV
Date: 12-2001
Tubulin/microtubule system as an anti-cancer drug target
Publisher: Bentham Science Publishers Ltd.
Date: 12-2007
ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties
Publisher: American Association for Cancer Research (AACR)
Date: 05-2010
DOI: 10.1158/1535-7163.MCT-09-0894
Abstract: The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrow–derived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug. Mol Cancer Ther 9(5) 1408–18. ©2010 AACR.
Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.JPROT.2013.10.032
Abstract: The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN(+/+) mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma s les, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN(+/+) mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma s les when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.
Antisense oligonucleotides to class III β-tubulin sensitize drug-resistant cells to Taxol
Publisher: Springer Science and Business Media LLC
Date: 07-05-1999
Identification of glycan structure alterations on cell membrane proteins in desoxyepothilone B resistant leukemia cells
Publisher: Elsevier BV
Date: 11-2011
Correction to “Effective Delivery of siRNA into Cancer Cells and Tumors Using Well-Defined Biodegradable Cationic Star Polymers”
Publisher: American Chemical Society (ACS)
Date: 18-02-2015
Improving the Targeting of Tubulin-Binding Agents: Lessons from Drug Resistance Studies
Publisher: Bentham Science Publishers Ltd.
Date: 05-2005
Abstract: Natural product drugs that target the tubulin/microtubule system remain an important component in the therapeutic arsenal to treat many types of malignancies. Agents such as the taxanes and vinca alkaloids bind to beta-tubulin and disrupt microtubule dynamics by inducing a potent mitotic block and subsequent cell death. Understanding why certain cancers do not respond to treatment or develop resistance has been the subject of numerous studies in recent years. An increasing body of evidence suggests that alterations in the drug target, such as tubulin mutations, altered microtubule dynamics, altered tubulin isotype expression, and modifications in microtubule regulatory proteins, are key mechanisms of antimicrotubule drug resistance. In addition, recent work indicates that other cytoskeletal proteins that can regulate microtubule dynamics through signaling or structural interactions may be important determinants of antimicrotubule resistance. As our understanding of drug action and resistance mechanisms has increased, we can now begin to exploit these to design strategies that overcome, or counteract resistance, hence improving the efficacy of antimicrotubule agents for the treatment of cancer. This review highlights the major areas of investigation as they relate to the tubulin/microtubule system and discusses opportunities that potentially exist for improved therapeutic benefit in the treatment of drug resistant disease.
Markedly diminished drug resistance-inducing properties of vinflunine (20′,20′-difluoro-3′,4′-dihydrovinorelbine) relative to vinorelbine, identified in murine and human tumour cells in vivo and in vitro
Publisher: Springer Science and Business Media LLC
Date: 07-2001
Abstract: Vinflunine (VFL) is a novel Vinca alkaloid with markedly superior experimental in vivo antitumour activity to its parent molecule, vinorelbine (Navelbine, NVB), against a panel of murine and human tumours. The aim of this study was to establish whether there are differences in the rate and extent of development of resistance, both in vivo and in vitro, to these two newer Vinca alkaloids under identical selection conditions. Using P388 leukaemia cells in vivo, it was evident that VFL induced drug resistance far less readily than NVB, as shown by the number of passages required to select for total resistance. Under in vitro conditions, using A549 human lung carcinoma cells, it was also clearly shown by drug sensitivity determinations that VFL was a less-potent inducer of drug resistance than NVB. Resistance resulting from either in vivo or in vitro selection was associated with a classic multidrug resistance profile. Further characterization of the drug-resistance phenotype of the most highly resistant A549 sublines showed that the level of total beta-tubulin expression appeared to be modified exclusively in the NVB-resistant cells. The clear demonstration that resistance to VFL developed far less readily than resistance to NVB both in vivo and in vitro may have potential clinical implications.
The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4BM00224E
Abstract: Previously synthesized poly(methacrylic acid- co -cholesteryl methacrylate) P(MAA- co -CMA) copolymers were examined as potential drug delivery vehicles.
A recombinant antibody fragment directed to the thymic stromal lymphopoietin receptor (CRLF2) efficiently targets pediatric Philadelphia chromosome-like acute lymphoblastic leukemia
Publisher: Elsevier BV
Date: 11-2021
Biologically Targeted Magnetic Hyperthermia: Potential and Limitations
Publisher: Frontiers Media SA
Date: 02-08-2018
Nanoparticles for radiooncology: Mission, vision, challenges
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.BIOMATERIALS.2016.12.010
Abstract: Cancer is one of the leading non-communicable diseases with highest mortality rates worldwide. About half of all cancer patients receive radiation treatment in the course of their disease. However, treatment outcome and curative potential of radiotherapy is often impeded by genetically and/or environmentally driven mechanisms of tumor radioresistance and normal tissue radiotoxicity. While nanomedicine-based tools for imaging, dosimetry and treatment are potential keys to the improvement of therapeutic efficacy and reducing side effects, radiotherapy is an established technique to eradicate the tumor cells. In order to progress the introduction of nanoparticles in radiooncology, due to the highly interdisciplinary nature, expertise in chemistry, radiobiology and translational research is needed. In this report recent insights and promising policies to design nanotechnology-based therapeutics for tumor radiosensitization will be discussed. An attempt is made to cover the entire field from preclinical development to clinical studies. Hence, this report illustrates (1) the radio- and tumor-biological rationales for combining nanostructures with radiotherapy, (2) tumor-site targeting strategies and mechanisms of cellular uptake, (3) biological response hypotheses for new nanomaterials of interest, and (4) challenges to translate the research findings into clinical trials.
Spatio-temporal analysis of nanoparticles in live tumor spheroids impacted by cell origin and density
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JCONREL.2021.12.014
Abstract: Nanoparticles hold great preclinical promise in cancer therapy but continue to suffer attrition through clinical trials. Advanced, three dimensional (3D) cellular models such as tumor spheroids can recapitulate elements of the tumor environment and are considered the superior model to evaluate nanoparticle designs. However, there is an important need to better understand nanoparticle penetration kinetics and determine how different cell characteristics may influence this nanoparticle uptake. A key challenge with current approaches for measuring nanoparticle accumulation in spheroids is that they are often static, losing spatial and temporal information which may be necessary for effective nanoparticle evaluation in 3D cell models. To overcome this challenge, we developed an analysis platform, termed the Determination of Nanoparticle Uptake in Tumor Spheroids (DONUTS), which retains spatial and temporal information during quantification, enabling evaluation of nanoparticle uptake in 3D tumor spheroids. Outperforming linear profiling methods, DONUTS was able to measure silica nanoparticle uptake to 10 μm accuracy in both isotropic and irregularly shaped cancer cell spheroids. This was then extended to determine penetration kinetics, first by a forward-in-time, center-in-space model, and then by mathematical modelling, which enabled the direct evaluation of nanoparticle penetration kinetics in different spheroid models. Nanoparticle uptake was shown to inversely relate to particle size and varied depending on the cell type, cell stiffness and density of the spheroid model. The automated analysis method we have developed can be applied to live spheroids in situ, for the advanced evaluation of nanoparticles as delivery agents in cancer therapy.
Polyphenol Conjugates by Immobilized Laccase: The Green Synthesis of Dextran‐Catechin
Publisher: Wiley
Date: 06-05-2016
Master Regulator Analysis from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426419
Abstract: Methods for Master Regulator Analysis
Frontiers in the treatment of glioblastoma: Past, present and emerging
Publisher: Elsevier BV
Date: 04-2021
Figure S3 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426434.V1
Abstract: Effect of copper levels on EGFR phosphorylation and PD-L1 protein stability
Microtubule Dynamics, Mitotic Arrest, and Apoptosis: Drug-Induced Differential Effects of βIII-Tubulin
Publisher: American Association for Cancer Research (AACR)
Date: 05-2010
DOI: 10.1158/1535-7163.MCT-09-0679
Abstract: Overexpression of βIII-tubulin is associated with resistance to tubulin-binding agents (TBA) in a range of tumor types. We previously showed that small interfering RNA silencing of βIII-tubulin expression hypersensitized non–small cell lung cancer cells to TBAs. To determine whether βIII-tubulin mediates its effect on drug-induced mitotic arrest and cell death by differentially regulating microtubule behavior, the effects of βIII-tubulin knockdown on microtubule dynamics were analyzed in H460 non–small cell lung cancer cells stably expressing green fluorescent protein-βI-tubulin. Interphase cells were examined at three vincristine and paclitaxel concentrations that (a) inhibited cell proliferation, (b) induced 5% to 10% mitotic arrest, and (c) induced 30% to 40% mitotic arrest. In the absence of either drug, βIII-tubulin knockdown caused no significant change in microtubule dynamic instability. At 2 nmol/L vincristine (IC50), overall microtubule dynamicity was significantly suppressed in βIII-tubulin knockdowns (−31.2%) compared with controls (−6.5%). Similar results were obtained with paclitaxel, suggesting that knockdown of βIII-tubulin induces hypersensitivity by enhancing stabilization of microtubule dynamics at low drug concentrations. At higher drug concentrations (≥40 nmol/L vincristine ≥20 nmol/L paclitaxel), βIII-tubulin knockdown resulted in significantly reduced suppressive effects on microtubule dynamicity with little or no further increase in mitotic arrest, compared with control cells. Importantly, apoptosis was markedly increased by βIII-tubulin knockdown independent of further suppression of microtubule dynamics and mitotic arrest. These results show that βIII-tubulin knockdown enhances the effectiveness of TBAs through two mechanisms: suppression of microtubule dynamics at low drug concentrations and a mitosis-independent mechanism of cell death at higher drug concentrations. Mol Cancer Ther 9(5) 1339–48. ©2010 AACR.
Figure S1 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426440.V1
Abstract: Co-expression plots of VST-normalized gene expression profiles derived from TCGA datasets for PD-L1 and four copper-responsive genes
Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors
Publisher: Springer Science and Business Media LLC
Date: 12-03-2021
DOI: 10.1038/S41419-020-03269-0
Abstract: Targeting cell ision by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell ision, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.
Tuneable catechin functionalisation of carbohydrate polymers
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.CARBPOL.2017.04.032
Abstract: In this contribution, we present a strategy to functionalise three natural carbohydrate polymers (dextran - a neutral polymer, sodium alginate - an anionic polymer and chitosan - a cationic polymer) with catechin with excellent degrees of functionality. In a first step, the carbohydrate polymers were oxidised by sodium periodate to yield aldehyde functionalised carbohydrate polymers. The presence of aldehyde groups was exploited to attach catechin by an acid catalysed nucleophilic reaction. The degree of catechin functionalisation could be easily tuned by varying the acid concentration in the reaction mixture, achieving catechin functionalisation levels of up to 48% for dextran aldehyde catechin, 35% for chitosan-aldehyde-catechin and 22% for sodium alginate aldehyde catechin.
Figure S5 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426428.V1
Abstract: DC increases tumor-infiltrating immune cells in Th-MYCN mice
On the evolution and modelling of brass-type texture in cold-rolled twinning-induced plasticity steel
Publisher: Elsevier BV
Date: 05-2014
Characterization of Mechanisms Mediating Drug Resistance in Human Leukemic Cells Selected with High Concentration Methotrexate
Publisher: Walter de Gruyter GmbH
Date: 02-1991
Positive- and negative-ion mass spectrometry of butyrophenones
Publisher: Elsevier BV
Date: 1986
DOI: 10.1016/S0378-4347(00)83512-4
Abstract: Positive-ion electron-impact (EI), positive-ion chemical ionization (CI) and medium-pressure negative-ion CI mass spectra of ten butyrophenones are presented. Low-pressure (0.01 Torr) negative CI spectra are also presented for some compounds. In the positive EI mode, a peak at m/z 42, which corresponded to the propyl group, appeared for all compounds a peak at m/z 123 was also common to all compounds except for the two with a bis(fluorophenyl) group. Molecular ions were generally very small or missing in the positive EI mode. In the positive CI mode, strong [M+H]+ quasi-molecular peaks generally appeared together with [M+C2H5]+ peaks [M-F]+ peaks appeared in many compounds and [M-OH]+ peaks also appeared for compounds having a hydroxypiperidinyl group. In the negative CI mode with a 1 Torr chamber pressure, their spectra were generally simple with [M-H]- quasi-molecular ions anions of liberated halogens were not observed except for bromine at this pressure. In the negative CI mode at low pressure (0.01 Torr), some fragment peaks in the lower mass range appeared in addition to the quasi-molecular ions halogen peaks (m/z 19 or 35) and anions at m/z 95, which corresponded to the fluorophenyl group, appeared in most spectra recorded at this pressure. An procedure for the extraction of butyrophenones from human urine and plasma and their separation by gas chromatography was also developed to serve for their identification in forensic science practice.
Comparison of different irrigation methods to synergistically improve maize’s yield, water productivity and economic benefits in an arid irrigation area
Publisher: Elsevier BV
Date: 2021
TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization
Publisher: Informa UK Limited
Date: 19-02-2013
DOI: 10.4161/CC.23825
Clinical Studies With Epothilones for the Treatment of Metastatic Breast Cancer
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1053/J.SEMINONCOL.2008.02.003
Abstract: Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.
Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β‐tubulins
Publisher: Wiley
Date: 23-03-2007
DOI: 10.1002/IJC.22557
Abstract: The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. The relevance of the Class I beta-tubulin characteristics have also been confirmed in the clinical setting where mutations of paclitaxel-binding site of beta-tubulin Class I have been related to paclitaxel resistance in non small cell lung and ovarian cancers. In the present study, we verified the hypothesis of a relationship between molecular alterations of beta-tubulin Class I and paclitaxel sensitivity in a panel of breast cell lines with different drug IC(50). The Class I beta-tubulin gene cDNA has been sequenced detecting heterozygous missense mutations (exon 1 and 4) only in MCF-7 and SK-BR-3 lines. Furthermore, the expression (at both mRNA and protein level) of the different isotypes have been analyzed demonstrating an association between low cell sensitivity to paclitaxel and Class III beta-tubulin expression increasing. Antisense oligonucleotide (ODN) experiments confirmed that the inhibition of Class III beta-tubulin could at least partially increase paclitaxel-chemosensitivity. The hypothesis of a relationship between beta-tubulin tumor expression and paclitaxel clinical response has been finally verified in a series of 92 advanced breast cancer patients treated with a first line paclitaxel-based chemotherapy. Thirty-five percent (95% CI: 45-31) of patients with high Class III beta-tubulin expression showed a disease progression vs. only 7% of patients with low expression (35% vs. 7%, p < 0.002). Our study suggests that Class III beta-tubulin tumor expression could be considered a predictive biomarker of paclitaxel-clinical resistance for breast cancer patients.
A novel plant toxin, persin, within vivoactivity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells
Publisher: American Association for Cancer Research (AACR)
Date: 09-2006
DOI: 10.1158/1535-7163.MCT-06-0170
Abstract: Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor–, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland–specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers. [Mol Cancer Ther 2006 (9):2300–9]
Drug delivery: Beyond active tumour targeting
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.NANO.2014.04.012
Abstract: Despite improvements in our understanding of cancer and the concept of personalised medicine, cancer is still a major cause of death. It is established that solid tumours are highly heterogeneous, with a complex tumour microenvironment. Indeed, the tumour microenvironment is made up of a collection of immune cells, cancer-activated fibroblasts, and endothelial cells and in some cases a dense extracellular matrix. Accumulating evidence shows that the tumour microenvironment is a major barrier for the effective delivery of therapeutic drugs to tumour cells. Importantly, nanotechnology has come to the forefront as highly effective delivery vehicles for therapeutic agents. This perspective will discuss how nanomedicine can be used to target and deliver therapeutic drugs specifically to tumour cells. Moreover, emerging opportunities to modulate the tumour microenvironment and increase the delivery and efficacy of chemotherapy agents to solid tumours will be highlighted. Improving drug delivery to treatment resistant tumors is a major target of many nanomedicine-based applications. This comprehensive review discusses the currently available and emerging opportunities, in addition to discussing tumor microenvironment modulation to facilitate efficient delivery.
The role of β-tubulin isotypes in resistance to antimitotic drugs
Publisher: Elsevier BV
Date: 2001
Proteomics and disease: opportunities and challenges.
Publisher: AMPCo
Date: 06-2005
DOI: 10.5694/J.1326-5377.2005.TB06817.X
Abstract: Since the human genome was sequenced, there has been intense activity to understand the function of the 30,000 identified genes attention has now turned to the products of genes--proteins. Proteomics is the large-scale study of the structure and function of proteins it includes the rapidly evolving field of disease proteomics, which aims to identify proteins involved in human disease and to understand how their expression, structure and function cause illness. Proteomics has identified proteins that offer promise as diagnostic or prognostic markers, or as therapeutic targets in a range of illnesses, including cancer, immune rejection after transplantation, and infectious diseases such as tuberculosis and malaria it has the potential to allow patient-tailored therapy. Some major challenges remain, both technical (eg, detecting "low-abundance" proteins, and maintaining s le stability) and in data management (eg, correlating changes in proteins with disease processes).
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