ORCID Profile
0000-0002-4742-4690
Current Organisation
University of New South Wales Science
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 03-01-2013
DOI: 10.1038/BJC.2012.582
Publisher: Impact Journals, LLC
Date: 18-09-2015
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.BBCAN.2016.07.004
Abstract: Progesterone receptor membrane component 1 (PGRMC1) is a multi-functional protein with a heme-binding moiety related to that of cytochrome b
Publisher: Springer Science and Business Media LLC
Date: 27-09-2016
DOI: 10.1186/S13045-016-0330-X
Abstract: Neuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches. A novel anti-cancer agent of the di-2-pyridylketone thiosemicarbazone series, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), demonstrates promising anti-tumor activity. Recently, a second-generation analogue, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), has entered multi-center clinical trials for the treatment of advanced and resistant tumors. The current aim was to examine if these novel agents were effective against aggressive neuroblastoma in vitro and in vivo and to assess their mechanism of action. Neuroblastoma cancer cells as well as immortalized normal cells were used to assess the efficacy and selectivity of DpC in vitro. An orthotopic SK-N-LP/Luciferase xenograft model was used in nude mice to assess the efficacy of DpC in vivo. Apoptosis in tumors was confirmed by Annexin V/PI flow cytometry and H&E staining. DpC demonstrated more potent cytotoxicity than Dp44mT against neuroblastoma cells in a dose- and time-dependent manner. DpC significantly increased levels of phosphorylated JNK, neuroglobin, cytoglobin, and cleaved caspase 3 and 9, while decreasing IkBα levels in vitro. The contribution of JNK, NF-ĸB, and caspase signaling/activity to the anti-tumor activity of DpC was verified by selective inhibitors of these pathways. After 3 weeks of treatment, tumor growth in mice was significantly (p < 0.05) reduced by DpC (4 mg/kg/day) given intravenously and the agent was well tolerated. Xenograft tissues showed significantly higher expression of neuroglobin, cytoglobin, caspase 3, and tumor necrosis factor-α (TNFα) levels and a slight decrease in interleukin-10 (IL-10). DpC was found to be highly potent against neuroblastoma, demonstrating its potential as a novel therapeutic for this disease. The ability of DpC to increase TNFα in tumors could also promote the endogenous immune response to mediate enhanced cancer cell apoptosis.
Publisher: Bentham Science Publishers Ltd.
Date: 03-2011
DOI: 10.2174/156802611794785190
Abstract: Cancer is one of the leading causes of death worldwide and there is an increasing need for novel anti-tumor therapeutics with greater selectivity and potency. A new strategy in the treatment of cancer has focused on targeting an essential cell metabolite, iron (Fe). Iron is vital for cell growth and metabolism, forming a crucial component of the active site of ribonucleotide reductase (RR), the rate-limiting enzyme in DNA synthesis. Cancer cells in particular require large amounts of Fe to proliferate, making them more susceptible to the Fe deficiency caused by Fe chelators. Beginning with primordial siderophores, Fe chelators have since evolved to a new generation of potent and efficient anti-cancer agents. Recently, investigations have led to the generation of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands that demonstrate marked and selective anti-tumor activity both in vitro and in vivo against a wide spectrum of tumors. The mechanism of action of these novel ligands includes alterations in the expression of key regulatory molecules as well as the generation of redox active Fe complexes. Interestingly, non-synthetic Fe chelators including silybin and curcumin, both of which are derived from plants, also have vast potential in the treatment of cancer. This review explores the development of novel Fe chelators for the treatment of cancer and their mechanisms of action.
Publisher: Elsevier BV
Date: 05-2018
Publisher: The Company of Biologists
Date: 2014
DOI: 10.1242/JCS.147835
Abstract: N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor-β (TGF-β)-induced epithelial mesenchymal transition (EMT) by maintaining E-cadherin and β-catenin at the cell membrane in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrated that NDRG1 inhibited the phosphorylation of β-catenin at Ser33/37, Thr41 and increased non-phosphorylated β-catenin levels on the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting β-catenin phosphorylation involved the NDRG1-mediated up-regulation of the GSK3β-binding protein, FRAT1, which prevents the association of GSK3β with the Axin1/APC/CK1 destruction complex and subsequent phosphorylation of β-catenin. Additionally, NDRG1 was shown to modulate the WNT/β-catenin pathway by inhibiting β-catenin nuclear translocation. This was mediated through its effect of reducing the nuclear localization of p21 activated kinase 4 (PAK4), which is known to act as a transporter for β-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the regulation of β-catenin phosphorylation and distribution by NDRG1.
Publisher: American Chemical Society (ACS)
Date: 07-01-2011
DOI: 10.1021/TX100435C
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BBAGEN.2017.10.009
Abstract: The cyclin-dependent kinase inhibitor, p21, is well known for its role in cell cycle arrest. Novel anti-cancer agents that deplete iron pools demonstrate marked anti-tumor activity and are also active in regulating p21 expression. These agents induce p21 mRNA levels independently of the tumor suppressor, p53, and differentially regulate p21 protein expression depending on the cell-type. Several chelators, including an analogue of the potent anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), have entered clinical trials, and thus, their molecular mechanism of action is crucial to assess. Hence, this investigation examined how several iron chelators transcriptionally regulate p21. Promoter-deletion constructs luciferase assays RT-PCR western analysis gene silencing co-immunoprecipitation. The transcriptional regulation of the p21 promoter by iron chelators was demonstrated to be dependent on the chelator and cell-type examined. The potent anti-cancer chelator, Dp44mT, induced p21 promoter activity in SK-MEL-28 melanoma cells, but not in MCF-7 breast cancer cells. Further analysis of the p21 promoter identified a 50-bp region between -104 and -56-bp that was required for Dp44mT-induced activation in SK-MEL-28 cells. This region contained several Sp1-binding sites and mutational analysis of this region revealed the Sp1-3-binding site played a significant role in Dp44mT-induced activation of p21. Further, co-immunoprecipitation demonstrated that Dp44mT induced a marked increase in the interactions between Sp1 and the transcription factors, estrogen receptor-α and c-Jun. Dp44mT-induced p21 promoter activation via the Sp1-3-binding site and increased Sp1/ER-α and Sp1/c-Jun complex formation in SK-MEL-28 cells, suggesting these complexes were involved in p21 promoter activation.
Publisher: Public Library of Science (PLoS)
Date: 21-02-2013
Publisher: American Chemical Society (ACS)
Date: 31-12-2016
DOI: 10.1021/ACS.JMEDCHEM.5B01399
Abstract: Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent.
Publisher: Wiley
Date: 26-07-2020
Publisher: Impact Journals, LLC
Date: 27-09-2015
Publisher: BMJ
Date: 08-06-2013
DOI: 10.1136/JCLINPATH-2013-201692
Abstract: N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BBAMCR.2016.04.017
Abstract: The potent and selective anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), localizes in lysosomes and forms cytotoxic copper complexes that generate reactive oxygen species (ROS), resulting in lysosomal membrane permeabilization (LMP) and cell death. Herein, the role of lysosomal membrane stability in the anti-tumor activity of Dp44mT was investigated. Studies were performed using molecules that protect lysosomal membranes against Dp44mT-induced LMP, namely heat shock protein 70 (HSP70) and cholesterol. Up-regulation or silencing of HSP70 expression did not affect Dp44mT-induced LMP in MCF7 cells. In contrast, cholesterol accumulation in lysosomes induced by the well characterized cholesterol transport inhibitor, 3-β-[2-(diethyl-amino)ethoxy]androst-5-en-17-one (U18666A), inhibited Dp44mT-induced LMP and markedly and significantly (p<0.001) reduced the ability of Dp44mT to inhibit cancer cell proliferation (i.e., increased the IC(50)) by 140-fold. On the other hand, cholesterol extraction using methyl-β-cyclodextrin enhanced Dp44mT-induced LMP and significantly (p<0.01) increased its anti-proliferative activity. The protective effect of U18666A in increasing lysosomal cholesterol and preventing the cytotoxic activity of Dp44mT was not due to induced autophagy. Instead, U18666A was found to decrease lysosomal turnover, resulting in autophagosome accumulation. Moreover, preincubation with U18666A did not prevent the ability of Dp44mT to induce autophagosome synthesis, indicating that autophagic initiation via Dp44mT occurs independently of LMP. These studies demonstrate the significance of lysosomal membrane stability in relation to the ability of Dp44mT to execute tumor cell death and overcome pro-survival autophagy. Hence, lysosomal-dependent cell death induced by Dp44mT serves as an important anti-tumor strategy. These results are important for comprehensively understanding the mechanism of action of Dp44mT.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.BMCL.2012.07.030
Abstract: Iron chelators have emerged as a potential anti-cancer treatment strategy. In this study, a series of novel thiosemicarbazone iron chelators containing a quinoline scaffold were synthesized and characterized. A number of analogs show markedly greater anti-cancer activity than the 'gold-standard' iron chelator, desferrioxamine. The anti-proliferative activity and iron chelation efficacy of several of these ligands (especially compound 1b), indicates that further investigation of this class of thiosemicarbazones is worthwhile.
Publisher: Mary Ann Liebert Inc
Date: 10-03-2013
Abstract: The metastasis suppressor gene, N-myc downstream regulated gene-1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, including pancreatic cancer. Moreover, NDRG1 is an iron-regulated gene that is markedly upregulated by cellular iron-depletion using novel antitumor agents such as the chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), in pancreatic cancer cells. However, the exact function(s) of NDRG1 remain to be established and are important to elucidate. In the current study, using gene-array analysis along with NDRG1 overexpression and silencing, we identified the molecular targets of NDRG1 in three pancreatic cancer cell lines. We demonstrate that NDRG1 upregulates neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) and GLI-similar-3 (GLIS3). Further studies examining the downstream effects of NEDD4L led to the discovery that NDRG1 affects the transforming growth factor-β (TGF-β) pathway, leading to the upregulation of two key tumor suppressor proteins, namely phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and mothers against decapentaplegic homolog-4 (SMAD4). Moreover, NDRG1 inhibited the phosphatidylinositol 3-kinase (PI3K) and Ras oncogenic pathways. This study provides significant insights into the mechanisms underlying the antitumor activity of NDRG1. For the first time, a role for NDRG1 is established in regulating the key signaling pathways involved in oncogenesis (TGF-β, PI3K, and Ras pathways). The identified target genes of NDRG1 and their effect on the TGF-β signaling pathway reveal its molecular function in pancreatic cancer and a novel therapeutic avenue.
Publisher: Future Science Ltd
Date: 04-2015
DOI: 10.4155/FMC.15.15
Publisher: Mary Ann Liebert Inc
Date: 10-03-2018
Abstract: Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.BBAGEN.2019.04.017
Abstract: Angiogenesis is essential for tumor growth, proliferation and metastasis. Tumor-related angiogenesis is complex and involves multiple signaling pathways. Controlling angiogenesis is a promising strategy for limiting cancer progression. Several receptor tyrosine kinases influence the angiogenic response via multiple signaling molecules and pathways. Understanding the functional interaction of kinases in the angiogenic process and development of resistance to kinase inhibition is essential for future successful therapeutic strategies. Strategies that target receptor tyrosine kinases and other tumor microenvironment factors simultaneously, or sequentially, are required for achieving an efficient and robust anti-angiogenic response. Understanding the molecular mechanism of angiogenesis has improved, and has led, to the clinical development and approval of anti-angiogenic drugs. While many patients have benefited from these agents, their limited efficacy and the development of resistance remains a challenge. This review highlights current therapies and challenges associated with targeting angiogenesis in cancer.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.PHRS.2016.12.001
Abstract: Metastasis is currently the leading cause of cancer related death and is the most feared and difficult to treat outcome for cancer patients. This complex process is regulated by a plethora of signaling pathways and molecules that control cell proliferation, invasion, motility and adhesion. Many of these vital processes that enable metastasis to occur are influenced by metals, which play crucial roles in the function of numerous proteins and enzymes. Importantly, an excess of essential metals such as iron and copper is often associated with carcinogenesis and metastatic disease. As such, metals have emerged as promising and viable therapeutic targets for a new generation of anti-cancer and anti-metastatic agents. Further, the unique properties of metals, including their abilities to redox cycle or to mimic other metals, can also be utilized to more effectively target aggressive and metastatic cancer cells. This review will provide an overview of the role that metals play in the metastatic progression of cancer and the development of novel therapies that either target or utilize metal ions as part of their mechanism of action to inhibit metastasis.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2012
DOI: 10.2174/092986712800609706
Abstract: The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also apoptosis. In addition, many iron chelators are known to inhibit ribonucleotide reductase, the iron-containing enzyme that is the rate-limiting step for DNA synthesis. Desferrioxamine is a well known chelator used for the treatment of iron-overload disease, but it has also been shown to possess anti-cancer activity. Another class of chelators, namely the thiosemicarbazones, have been shown to possess anti-cancer activity since the 1950's, although their mechanism(s) of action have only recently been more comprehensively elucidated. In fact, the redox activity of thiosemicarbazone iron complexes is thought to be important in mediating their potent cytotoxicity. Moreover, unlike typical iron chelators which simply act to deplete tumors of iron, several thiosemicarbazones (i.e., Bp44mT and Dp44mT) do not induce this effect, their anti-cancer efficacy being due to other mechanisms e.g., redox activity. Other reports have also shown that some thiosemicarbazones inhibit topoisomerase IIα, demonstrating that this class of agents have multiple molecular targets and act by various mechanisms. The most well characterized thiosemicarbazone iron chelator in terms of its assessment in humans is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Observations from these clinical trials highlight the less than optimal activity of this ligand and several side effects related to its use, including myelo-suppression, hypoxia and methemoglobinemia. The mechanisms responsible for these latter effects must be elucidated and the design of the ligand altered to minimize these problems and increase efficacy. This review discusses the development of chelators as unique agents for cancer treatment.
Publisher: Impact Journals, LLC
Date: 22-08-2015
Publisher: Elsevier BV
Date: 12-2016
Publisher: Begell House
Date: 2013
DOI: 10.1615/CRITREVONCOG.2013007921
Abstract: Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide in both men and women. It presents late with non-specific symptoms, which makes it difficult to diagnose until the cancer has progressed and metastasized. Metastasis is facilitated by the epithelial-to-mes-enchymal transition (EMT), which is promoted via the oncogenic transforming growth factor beta (TGFβ), Wnt, and nuclear factor kappa B (NFκB) signaling pathways. However, recent studies have demonstrated that the EMT can be inhibited by novel anti-cancer agents known as thiosemicarbazone iron chelators. These novel agents also up-regulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which can restore normal signaling to the cell and suppresses metastasis via inhibition of the EMT. Through the ability of iron chelators to up-regulate NDRG1 expression and affect multiple molecular targets, these agents have the potential to maintain the epithelial phenotype of cancer cells and may lead to improved survival rates for patients with late-stage disease.
Publisher: Oxford University Press (OUP)
Date: 11-03-2011
Abstract: The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), has been shown to markedly reduce metastasis of numerous tumors. The current study was focused on further elucidating the molecular mechanisms behind the antitumor function of NDRG1. We have identified for the first time that NDRG1 upregulates the potent cyclin-dependent kinase inhibitor, p21. This effect was observed in three different cancer cell types, including PC3MM and DU145 prostate cancer cells and H1299 lung carcinoma cells, and occurred independently of p53. In addition, reducing NDRG1 expression using short hairpin RNA in PC3MM and DU145 cells resulted in significantly reduced p21 protein levels. Hence, p21 is closely correlated with NDRG1 expression in these latter cell types. Examining the mechanisms behind the effect of NDRG1 on p21 expression, we found that NDRG1 upregulated p21 via transcriptional and posttranscriptional mechanisms in prostate cancer cells, although its effect on H1299 cells was posttranscriptional only. Further studies identified two additional NDRG1 protein targets. The dominant-negative p63 isoform, ΔNp63, which has been found to inhibit p21 transcription, was downregulated by NDRG1. On the other hand, a truncated 50 kDa MDM2 isoform (p50(MDM2)), which may protect p21 from proteasomal degradation, was upregulated by NDRG1. The downregulation of ΔNp63 and upregulation of p50(MDM2) are potential mechanisms by which NDRG1 increases p21 expression in these cells. Additional functional studies identified that NDRG1 inhibits cancer cell migration, suggesting that p21 is a molecular player in its antimetastatic activity.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 08-03-2017
Abstract: Tumor necrosis factor
Publisher: Wiley
Date: 04-2012
Publisher: Bentham Science Publishers Ltd.
Date: 14-03-2019
DOI: 10.2174/0929867324666170705120809
Abstract: Metals are vital cellular elements necessary for multiple indispensable biological processes of living organisms, including energy transduction and cell proliferation. Interestingly, alterations in metal levels and also changes in the expression of proteins involved in metal metabolism have been demonstrated in a variety of cancers. Considering this and the important role of metals for cell growth, the development of drugs that sequester metals has become an attractive target for the development of novel anti-cancer agents. Interest in this field has surged with the design and development of new generations of chelators of the thiosemicarbazone class. These ligands have shown potent anticancer and anti-metastatic activity in vitro and in vivo. Due to their efficacy and safe toxicological assessment, some of these agents have recently entered multi-center clinical trials as therapeutics for advanced and resistant tumors. This review highlights the role and changes in homeostasis of metals in cancer and emphasizes the pre-clinical development and clinical assessment of metal ion-binding agents, namely, thiosemicarbazones, as antitumor agents.
Publisher: Future Science Ltd
Date: 05-2016
Publisher: Wiley
Date: 19-11-2009
Publisher: American Association for Cancer Research (AACR)
Date: 11-2011
DOI: 10.1158/1535-7163.TARG-11-A67
Abstract: Iron is known to be important for cell cycle progression and intracellular iron (Fe) chelation has been shown to down-regulate the expression of the cyclin-dependent kinase inhibitor, p21CIP1/WAF1 (p21) in MCF-7 breast cancer cells [1]. p21 has been demonstrated to have both positive and negative effects on G1/S cell cycle progression and regulate cancer cell apoptosis and senescence [2, 3]. Our preliminary studies have suggested that Fe-depletion affects p21 expression differentially depending upon the cell type. Therefore, understanding the ability of Fe chelators to regulate the expression of p21 differently in cancer cells and the biological consequences thereof may provide an insight into the mechanisms involved in the anti-tumor efficacy of these agents. The current study examined the mechanisms involved in regulating p21 expression by Fe in a number of cancer cell-types with different p53 status. RT-PCR demonstrated an increase in p21 mRNA levels in all cells in response to Fe chelation. Western blotting demonstrated that the expression of p21 after incubation with chelators differed between the cell-types. Down-regulation in p21 protein expression was observed in the MCF-7 breast cancer and SK-N-MC neuroepithelioma cells, while up-regulation of p21 protein was evident in the SK-MEL-28 melanoma, CFPAC-1 pancreatic and LNCaP prostate cancer cell-types. However, the effect of the Fe chelator on p21 expression was not correlated to the p53 status of these cells. Furthermore, we showed that nuclear expression levels of p21 in cancer cells were much higher than cytoplasmic expression after Fe chelation. It has been shown that the variety of physiological roles that p21 plays, including cell cycle arrest, rely on its nuclear localisation [4]. These results were confirmed using cytoplasmic and nuclear fractionation, western analysis and immunofluorescence studies. The roles of MDM2 and Np63 in regulating p21 in response to Fe-depletion were also assessed, as these latter molecules can modulate p21 expression in a p53-independent manner [5, 6]. Results demonstrated that after incubation with Fe chelators, the expression pattern of the p75 isoform of MDM2 (p75MDM2) closely resembled that of p21 in 4 of the 5 cell lines investigated. This indicated that MDM2 may be one pathway through which these drugs regulate p21 expression. There was no significant change in Np63 expression after incubating these cells with Fe chelators, suggesting that the alterations in p21 expression observed were independent of Np63. Further studies are focusing on the possible transcriptional regulation of p21 by Fe-depletion. This is being carried out by using p21 promoter constructs to decipher the region of the p21 promoter that is involved in the Fe-regulated expression of p21. Overall, these studies will provide significant insight into the mechanism of action of Fe chelators at the molecular level. References: 1. Fu, D. and D.R. Richardson, Blood, 2007. 110(2): p. 752–61. 2. Ogryzko, V.V., et. al Mol Cell Biol, 1997. 17(8): p. 4877–82. 3. Gartel, A.L. and S.K. Radhakrishnan, Cancer Res, 2005. 65(10): p. 3980–5. 4. Child, E.S. and D.J. Mann, Cell Cycle, 2006. 5(12): p. 1313–9. 5. Zhang, Z., et al., J Biol Chem, 2004. 279(16): p. 16000–6. 6. Yang, A., et al., Mol Cell, 1998. 2(3): p. 305–16. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2011 Nov 12-16 San Francisco, CA. Philadelphia (PA): AACR Mol Cancer Ther 2011 (11 Suppl):Abstract nr A67.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 27-11-2012
Abstract: The iron-regulated metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), is up-regulated by cellular iron depletion mediated by iron chelators and can inhibit cancer cell migration. However, the mechanism of how NDRG1 achieves this effect remains unclear. In this study, we implemented established and newly constructed NDRG1 overexpression and knockdown models using the DU145, HT29, and HCT116 cancer cell lines to investigate the molecular basis by which NDRG1 exerts its inhibitory effect on cell migration. Using these models, we demonstrated that NDRG1 overexpression inhibits cell migration by preventing actin-filament polymerization, stress fiber assembly and formation. In contrast, NDRG1 knockdown had the opposite effect. Moreover, we identified that NDRG1 inhibited an important regulatory pathway mediated by the Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) hosphorylated myosin light chain 2 (pMLC2) pathway that modulates stress fiber assembly. The phosphorylation of MLC2 is a key process in inducing stress fiber contraction, and this was shown to be markedly decreased or increased by NDRG1 overexpression or knockdown, respectively. The mechanism involved in the inhibition of MLC2 phosphorylation by NDRG1 was mediated by a significant (P < 0.001) decrease in ROCK1 expression that is a key kinase involved in MLC2 phosphorylation. Considering that NDRG1 is up-regulated after cellular iron depletion, novel thiosemicarbazone iron chelators (e.g., di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone) were demonstrated to inhibit ROCK1 MLC2-modulated actin-filament polymerization, stress fiber assembly, and formation via a mechanism involving NDRG1. These results highlight the role of the ROCK1 MLC2 pathway in the NDRG1-mediated antimetastatic signaling network and the therapeutic potential of iron chelators at inhibiting metastasis.
Publisher: Impact Journals, LLC
Date: 07-08-2015
Publisher: Impact Journals, LLC
Date: 19-07-2016
Publisher: Informa UK Limited
Date: 15-08-2007
DOI: 10.4161/CC.6.16.4603
Abstract: Iron (Fe) is essential for cellular metabolism e.g., DNA synthesis and its depletion causes G(1)/S arrest and apoptosis. Considering this, Fe chelators have been shown to be effective anti-proliferative agents. In order to understand the anti-tumor activity of Fe chelators, the mechanisms responsible for G(1)/S arrest and apoptosis after Fe-depletion have been investigated. These studies reveal a multitude of cell cycle control molecules are regulated by Fe. These include p53, p27(Kip1), cyclin D1 and cyclin-dependent kinase 2(cdk2). Additionally, Fe-depletion up-regulates the mRNA levels of the cdk inhibitor, p21(CIP1/WAF1), but paradoxically down-regulates its protein expression. This effect could contribute to the apoptosis observed after Fe-depletion. Iron-depletion also leads to proteasomal degradation of p21(CIP1/WAF1) and cyclin D1 via an ubiquitin-independent pathway. This is in contrast to the mechanism in Fe-replete cells, where it occurs by ubiquitin-dependent proteasomal degradation. Up-regulation of p38 mitogen-activated protein kinase (MAPK) after Fe-depletion suggests another facet of cell cycle regulation responsible for inhibition of proliferation and apoptosis induction. Elucidation of the complex effects of Fe-depletion on the expression of cell cycle control molecules remains at its infancy. However, these processes are important to dissect for complete understanding of Fe-deficiency and the development of chelators for cancer treatment.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 05-01-2015
Abstract: Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.FREERADBIOMED.2019.05.020
Abstract: N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.PHRS.2015.08.013
Abstract: Cancer is a disease that is a "moving target", since as the condition progresses, the molecular targets change and evolve. Moreover, due to clonal selection, a specific anti-cancer drug with one molecular target may only be effective for a limited time period before drug resistance results and the agent becomes ineffective. Hence, the concept of an anti-tumor therapeutic exhibiting polypharmacology can be highly advantageous, rather than a therapeutic obstacle. A novel class of agents possessing these desirable properties are the di-2-pyridylketone thiosemicarbazones, which bind iron and copper to affect a variety of critical molecular targets in tumors. In fact, these compounds possess multiple properties that enable them to overcome the "triad of death" in cancer, namely: primary tumor growth, drug resistance and metastasis. In fact, at the molecular level, their potent anti-oncogenic activity includes: up-regulation of the metastasis suppressor, N-myc downstream regulated gene 1 up-regulation of the tumor suppressor, PTEN down-regulation of the proto-oncogene, cyclin D1 inhibition of the rate-limiting step in DNA synthesis catalyzed by ribonucleotide reductase and the inhibition of multiple oncogenic signaling pathways, e.g., Ras/MAPK signaling, protein kinase B (AKT) hosphatidylinositol-3-kinase, ROCK MLC2, etc. This Perspective article discusses the advantages of incorporating polypharmacology into anti-cancer drug design using the di-2-pyridylketone thiosemicarbazones as a pertinent ex le.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Impact Journals, LLC
Date: 23-06-2015
Abstract: Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer.
Publisher: Future Science Ltd
Date: 2012
DOI: 10.4155/FMC.11.178
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.BBAGEN.2017.02.021
Abstract: We recently demonstrated that a novel storage and transport mechanism for nitric oxide (NO) mediated by glutathione-S-transferase P1 (GSTP1) and multidrug resistance protein 1 (MRP1/ABCC1), protects M1-macrophage (M1-MØ) models from large quantities of endogenous NO. This system stores and transports NO as dinitrosyl-dithiol-iron complexes (DNICs) composed of iron, NO and glutathione (GSH). Hence, this gas with contrasting anti- and pro-tumor effects, which has been assumed to be freely diffusible, is a tightly-regulated species in M1-MØs. These control systems prevent NO cytotoxicity and may be responsible for delivering cytotoxic NO as DNICs via MRP1 from M1-MØs, to tumor cell targets.
Publisher: Impact Journals, LLC
Date: 25-02-2016
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 19-02-2016
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.FREERADBIOMED.2018.03.027
Abstract: Iron (Fe) has become an important target for the development of anti-cancer therapeutics with a number of Fe chelators entering human clinical trials for advanced and resistant cancer. An important aspect of the activity of these compounds is their multiple molecular targets, including those that play roles in arresting the cell cycle, such as the cyclin-dependent kinase inhibitor, p21. At present, the exact mechanism by which Fe chelators regulate p21 expression remains unclear. However, recent studies indicate the ability of chelators to up-regulate p21 at the mRNA level was dependent on the chelator and cell-type investigated. Analysis of the p21 promoter identified that the Sp1-3-binding site played a significant role in the activation of p21 transcription by Fe chelators. Furthermore, there was increased Sp1/ER-α and Sp1/c-Jun complex formation in melanoma cells, suggesting these complexes were involved in p21 promoter activation. Elucidating the mechanisms involved in the regulation of p21 expression in response to Fe chelator treatment in neoplastic cells will further clarify how these agents achieve their anti-tumor activity. It will also enhance our understanding of the complex roles p21 may play in neoplastic cells and lead to the development of more effective and specific anti-cancer therapies.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2021
DOI: 10.1186/S13058-020-01383-7
Abstract: An amendment to this paper has been published and can be accessed via the original article.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.BCP.2016.04.001
Abstract: The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP) (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)) (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP) and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment.
Publisher: Portland Press Ltd.
Date: 22-04-2016
DOI: 10.1042/CS20160072
Abstract: The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron–sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BBCAN.2013.11.002
Abstract: N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C6MT00105J
Abstract: Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.BBADIS.2019.02.008
Abstract: N-myc downstream regulated gene 1 (NDRG1) is an intriguing metastasis suppressor protein, which plays an important role in suppressing multiple oncogenic signaling pathways. Interestingly, multiple isoforms of NDRG1 have been identified, although the molecular mechanisms involved in their generation remains elusive. Herein, we demonstrate the role of two mechanisms involving autophagic and proteasomal machinery as part of an intricate system to generate different NDRG1 isoforms. Examining multiple pancreatic cancer cell-types using immunoblotting demonstrated three major isoforms of NDRG1 at approximately 41-, 46- and 47-kDa. The top NDRG1 band at 47-kDa was shown to be processed by the proteasome, followed by autophagic metabolism of the middle NDRG1 band at 46-kDa. The role of the proteasomal and autophagic pathways in NDRG1 processing was further confirmed by co-localization analysis of confocal images using PSMD9 and LC3 as classical markers of these respective pathways. All NDRG1 isoforms were demonstrated to be, at least in part, phosphorylated forms of the protein. Inhibition of two well-characterized upstream kinases of NDRG1, namely GSK3β and SGK1, resulted in decreased levels of the top NDRG1 band. Studies demonstrated that inhibition of GSK3β decreased levels of the top 47-kDa NDRG1 band, independent of its kinase activity, and this effect was not mediated via the proteasomal pathway. In contrast, the decrease in the top NDRG1 band at 47-kDa after SGK1 inhibition, was due to suppression of its kinase activity. Overall, these studies elucidated the complex and intricate regulatory pathways involving both proteasomal and autophagic processing of the metastasis suppressor protein, NDRG1.
Publisher: Oxford University Press (OUP)
Date: 18-12-2019
Abstract: The metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BBCAN.2014.01.005
Abstract: Cancer is a major public health issue and, despite recent advances, effective clinical management remains elusive due to intra-tumoural heterogeneity and therapeutic resistance. Iron is a trace element integral to a multitude of metabolic processes, including DNA synthesis and energy transduction. Due to their generally heightened proliferative potential, cancer cells have a greater metabolic demand for iron than normal cells. As such, iron metabolism represents an important "Achilles' heel" for cancer that can be targeted by ligands that bind and sequester intracellular iron. Indeed, novel thiosemicarbazone chelators that act by a "double punch" mechanism to both bind intracellular iron and promote redox cycling reactions demonstrate marked potency and selectivity in vitro and in vivo against a range of tumours. The general mechanisms by which iron chelators selectively target tumour cells through the sequestration of intracellular iron fall into the following categories: (1) inhibition of cellular iron uptake romotion of iron mobilisation (2) inhibition of ribonucleotide reductase, the rate-limiting, iron-containing enzyme for DNA synthesis (3) induction of cell cycle arrest (4) promotion of localised and cytotoxic reactive oxygen species production by copper and iron complexes of thiosemicarbazones (e.g., Triapine(®) and Dp44mT) and (5) induction of metastasis and tumour suppressors (e.g., NDRG1 and p53, respectively). Emerging evidence indicates that chelators can further undermine the cancer phenotype via inhibiting the epithelial-mesenchymal transition that is critical for metastasis and by modulating ER stress. This review explores the "expanding horizons" for iron chelators in selectively targeting cancer cells.
Publisher: American Chemical Society (ACS)
Date: 24-07-2019
DOI: 10.1021/ACS.INORGCHEM.9B01281
Abstract: A series of eight bis(thiosemicarbazone) ligands and 16 of their respective copper(II) and zinc(II) complexes containing a combination of hydrogen, methyl, pyridyl, phenyl, and/or ethyl substituents at the diimine position of the ligand backbone were synthesized and characterized. The objective of this study was to identify the structure-activity relationships within a series of analogues with different substituents at the diimine position of the backbone and at the terminal N atom. The Cu(II) complexes Cu(GTSM
Publisher: Public Library of Science (PLoS)
Date: 25-02-2016
Publisher: Elsevier BV
Date: 2016
Publisher: Wiley
Date: 23-01-2021
Publisher: Elsevier BV
Date: 03-2022
Publisher: Informa UK Limited
Date: 03-2013
Publisher: Public Library of Science (PLoS)
Date: 21-08-2012
Publisher: Oxford University Press (OUP)
Date: 18-08-2006
Abstract: Tumor metastasis is an important clinical problem, contributing to the majority of cancer-related deaths. The recent discovery of metastasis suppressor genes, such as N-myc downstream-regulated gene-1 (Ndrg-1), has introduced a novel approach to treating cancer and preventing metastasis. Ndrg-1 has been identified as a protein involved in the differentiation of epithelial cells. In addition, Ndrg-1 expression can be regulated by androgens and is involved in the pathology of the disease, Hereditary Motor and Sensory Neuropathy-Lom (HMSNL). However, one of the most well documented links between Ndrg-1 and pathophysiology is its association with inhibition of tumor metastasis. The expression of Ndrg-1 was found to be significantly downregulated in a variety of different neoplasms including breast, colon and prostate cancer. Furthermore, Ndrg-1 expression was shown to be negatively correlated with tumor metastasis. Studies in vitro and in vivo have demonstrated a significant reduction in the metastatic ability of cells overexpressing Ndrg-1. The ability of these cells to invade was also compromised. The Gleason grade of prostate and breast cancers was found to correlate with Ndrg-1 expression, with more advanced and poorly differentiated tumors having lower Ndrg-1 levels. Recently, Ndrg-1 expression was demonstrated to be regulated by cellular iron levels and induced by iron chelators. These latter compounds were recently identified as potential anticancer agents as they selectively prevent cancer cell proliferation and lead to apoptosis. The discovery that iron chelators also increase Ndrg-1 expression further augments their antitumor activity and provides a novel strategy for the treatment of cancer and its metastasis.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.FREERADBIOMED.2014.07.002
Abstract: Nitrogen monoxide (NO) is vital for many essential biological processes as a messenger and effector molecule. The physiological importance of NO is the result of its high affinity for iron in the active sites of proteins such as guanylate cyclase. Indeed, NO possesses a rich coordination chemistry with iron and the formation of dinitrosyl-dithiolato iron complexes (DNICs) is well documented. In mammals, NO generated by cytotoxic activated macrophages has been reported to play a role as a cytotoxic effector against tumor cells by binding and releasing intracellular iron. Studies from our laboratory have shown that two proteins traditionally involved in drug resistance, namely multidrug-resistance protein 1 and glutathione S-transferase, play critical roles in intracellular NO transport and storage through their interaction with DNICs (R.N. Watts et al., Proc. Natl. Acad. Sci. USA 103:7670-7675, 2006 H. Lok et al., J. Biol. Chem. 287:607-618, 2012). Notably, DNICs are present at high concentrations in cells and are biologically available. These complexes have a markedly longer half-life than free NO, making them an ideal "common currency" for this messenger molecule. Considering the many critical roles NO plays in health and disease, a better understanding of its intracellular trafficking mechanisms will be vital for the development of new therapeutics.
Publisher: Elsevier BV
Date: 05-2012
Publisher: American Association for Cancer Research (AACR)
Date: 11-2013
DOI: 10.1158/1535-7163.TARG-13-A232
Abstract: Background: Novel thiosemicarbazones that bind iron [i.e., di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) & di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC)] possess marked and selective anti-proliferative and anti-metastatic activities in vitro and in vivo across a range of cancer types [Proc Natl Acad Sci USA (2006) 103,14901-6 Mol Pharmacol (2011) 80,598-609]. However, the mechanisms underlying the anti-tumor effects of these compounds remain incompletely understood. Here, for the first time, we reveal that Dp44mT & DpC inhibit constitutive and interleukin 6 (IL6)-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which is hyper-activated in many malignancies and promotes proliferation, survival and metastasis of cancer cells. Methods: The pancreatic cancer cell lines, PANC-1 and MIAPaCa-2, and the prostate cancer cell line, DU145, were incubated with Dp44mT & DpC for 24 h/37°C. Following preparation of whole cell and compartmental protein extracts or native cell lysates, expression levels of proteins involved in STAT signaling were assessed by SDS-PAGE or native PAGE and immunoblotting. Results: Dp44mT & DpC significantly decreased constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in PANC-1, MIAPaCa-2, and DU145 cells. Furthermore, pre-incubation of these cells for 24 h with Dp44mT or DpC inhibited STAT3 phosphorylation and nuclear translocation induced by IL6. In MIAPaCa-2 cells, phosphorylation of the upstream non-receptor tyrosine kinase, Src, was also decreased by these agents. This observation indicated that the inhibition of STAT3 activation by Dp44mT or DpC may be mediated by non-receptor as well as receptor-mediated mechanisms. Using native PAGE, we showed that Dp44mT & DpC significantly decreased levels of dimerized STAT3, which was shown not to be due to direct binding of these compounds to STAT3. In addition, expression of STAT3-regulated gene products, namely cyclin D1 and c-myc, were significantly reduced. Redox-active Dp44mT- and DpC-iron complexes, but not the redox-inactive desferrioxamine-iron complex, also exhibited these inhibitory effects on the STAT pathway in all cell lines similarly to the ligands alone, suggesting that their redox activity was important for their effects. Collectively, these results indicate that Dp44mT & DpC suppress STAT3 transcriptional regulatory activity. Conclusions: Considering the role of IL6/STAT3 signaling in promoting tumorigenesis and tumor progression, these data reveal important insights into the mechanisms underlying the potent anti-cancer activity of Dp44mT and DpC through inhibition of the oncogenic STAT pathway. This knowledge may aid in the development of personalized cancer treatments based on the molecular signature of an in idual's cancer. Citation Information: Mol Cancer Ther 2013 (11 Suppl):A232. Citation Format: Goldie Y. L. Lui, Zaklina Kovacevic, Des R. Richardson. Novel thiosemicarbazones with potent antitumor and antimetastatic activity inhibit the signal transducer and activator of transcription (STAT) pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2013 Oct 19-23 Boston, MA. Philadelphia (PA): AACR Mol Cancer Ther 2013 (11 Suppl):Abstract nr A232.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2015
DOI: 10.1158/1535-7163.TARG-15-A63
Abstract: N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that has been shown to affect numerous signaling pathways that control oncogenesis. In this study, the role of NDRG1 was investigated on a key upstream effector, namely epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3). This is of interest, as the ErbB family of receptor tyrosine kinases are involved in regulating multiple cell responses, being key regulators of down-stream oncogenic-signaling. We demonstrate that NDRG1 is able to significantly reduce the expression, localisation and activation of EGFR, HER2 and HER3, while also inhibiting the formation of EGFR/HER2 and HER2/HER3 heterodimers. This investigation also showed that a novel class of anti-cancer agents, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), were able to markedly up-regulate NDRG1. These agents were found to inhibit EGFR, HER2 and HER3 expression and phosphorylation in PANC-1 pancreatic cancer cells in vitro. Moreover, these compounds led to a significant reduction of the expression of these proteins in PANC-1 tumour xenografts in vivo. Due to the limitations of current anti-cancer therapeutics, these agents were also compared to a clinically used EGFR inhibitor, Erlotinib. Our study showed that in comparison to Erlotinib, both Dp44mT and DpC displayed higher anti-proliferative activity in pancreatic cancer cells. This could be significant, as DpC is due to enter clinical trials this year for the treatment of aggressive solid tumours (ncochel/). Together, these findings reveal the molecular mechanisms that underlie the anti-cancer effects of NDRG1, and in turn, demonstrate the potential origin of the extensive down-stream effects attributed to this molecule. Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des R. Richardson. Role of the metastasis suppressor, NDRG1, in regulating the EGFR and ErbB family of receptors and its effects on key oncogenic signaling pathways in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2015 Nov 5-9 Boston, MA. Philadelphia (PA): AACR Mol Cancer Ther 2015 (12 Suppl 2):Abstract nr A63.
Publisher: American Association for Cancer Research (AACR)
Date: 13-12-2019
DOI: 10.1158/1538-7445.PANCA19-A16
Abstract: Background: Pancreatic cancer (PaCa) is a leading cause of cancer-related deaths and is projected to be the second most common cancer in a decade. It is characterized by a dense stroma surrounding tumor cells, known as desmoplasia that is stimulated by Sonic Hedgehog (SHH) released by PaCa cells. Stromal cells, in turn, release mitogenic substances such as hepatocyte growth factor (HGF) and Insulin-like growth factor receptor (IGF-1) by glioma-associated oncogene homolog 1 (GLI1) transcription factor that stimulate tumor growth, invasion, and resistance to therapy. We investigated the potential of targeting the metastasis suppressor gene N-myc downstream regulated gene 1 (NDRG1) to interrupt the oncogenic crosstalk between cancer associated human pancreatic stellate cells (PSCs) and PaCa cells. Methods: We assessed novel thiosemicarbazone anti-cancer agents, Dp44mT and DpC, that upregulate NDRG1 and their effects on: (i) SHH production by PaCa cells and also HGF and IGF-1 production by PSCs (ii) HGF and IGF-1 receptors and their downstream signaling in indirect 2D and direct 3D co-culture of PSCs and PaCa cells (iii) GLI1 and its upstream mediators in PSCs and (iv) proliferative and metastatic properties of PaCa cells co-cultured with PSCs. Results: Dp44mT and DpC upregulated NDRG1 and reduced SHH production by PaCa. These agents also inhibited downstream HGF and IGF-1 signaling pathways in PaCa cells, leading to reduced metastatic potential in co-culture 2D and 3D models. Further, these agents also inhibited GLI1 levels and activation in PSCs, leading to reduced HGF and IGF-1 production by these stromal cells. NDRG1 overexpression alone had similar effects, while silencing NDRG1 further potentiated the oncogenic crosstalk between PaCa and PSC cells. Conclusions: Novel agents targeting NDRG1 have the unique ability to block the oncogenic crosstalk between PaCa cells and the surrounding stroma. This presents a novel approach to PaCa treatment that can potentially overcome the major problems attributed to desmoplasia, including therapeutic resistance and metastasis. Citation Format: Bekesho Geleta, Kyung Chan Park, Patric J. Jansson, Minoti Apte, Des R. Richardson, Zaklina Kovacevic. A novel therapeutic approach to inhibit the bidirectional oncogenic crosstalk between pancreatic cancer cells and the surrounding stroma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care 2019 Sept 6-9 Boston, MA. Philadelphia (PA): AACR Cancer Res 2019 (24 Suppl):Abstract nr A16.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 23-05-2013
DOI: 10.1111/JRH.12024
Abstract: Health care-associated infection (HAI) is costly to hospitals and potentially life-threatening to patients. Numerous infection prevention programs have been implemented in hospitals across the United States. Yet, little is known about infection prevention practices and implementation in rural hospitals. The purpose of this study was to understand the infection prevention practices used by rural Veterans' Affairs (VA) hospitals and the unique factors they face in implementing these practices. This study used a sequential, mixed methods approach. Survey data to identify the HAI prevention practices used by rural VA hospitals were collected, analyzed, and used to inform the development of a semistructured interview guide. Phone interviews were conducted followed by site visits to rural VA hospitals. We found that most rural VA hospitals were using key recommended infection prevention practices. Nonetheless, a number of challenges with practice implementation were identified. The 3 most prominent themes were: (1) lack of human capital including staff with HAI expertise (2) having to cultivate needed resources and (3) operating as a system within a system. Rural VA hospitals are providing key infection prevention services to ensure a safe environment for the veterans they serve. However, certain factors, such as staff expertise, limited resources, and local context impacted how and when these practices were used. The creative use of more accessible alternative resources as well as greater flexibility in implementing HAI-related initiatives may be important strategies to further improve delivery of these important services by rural VA hospitals.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2009
DOI: 10.1158/1535-7163.TARG-09-B172
Abstract: A recently identified metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), has been shown to reduce the invasion and metastasis of numerous cancers including prostate (PC) and pancreatic (PaCa) (Maruyama Y et al. 2006 Cancer Res 66:6233–42) malignancies. Among its many functions, NDRG1 is involved in modulating differentiation, proliferation, and angiogenesis (Kovacevic Z & Richardson DR 2006 Carcinogenesis 27:2355–66). However, knowledge of the molecular function of NDRG1 is limited. We have recently discovered that NDRG1 is up-regulated in cancer cells by novel iron chelators being developed as anti-cancer agents in our lab (Richardson DR et al. Blood 2004 104:2967–75 Kovacevic Z et al. BBA 2008 1783:1981–92). These compounds were found to exhibit potent and selective anti-tumor activity in vivo (Richardson DR et al. PNAS USA 2006 103:14901–6). They also provide us with a unique opportunity to target this important metastasis suppressor in cancer tissues. The current study has focused on examining the molecular targets of NDRG1 in a number of different cancer cells to elucidate its anti-metastatic role. We further explored the efficacy of 2 novel iron chelators Bp4eT and Dp44mT, both of which up-regulate NDRG1, for the treatment of PaCa. We have identified for the first time that NDRG1 up-regulates protein levels of p21, a cyclin-dependant kinase inhibitor involved in controlling progression of the cell cycle. This effect was observed in three different cancer cell lines including PC3 and DU145 prostate cancer cells as well as H1299 lung cancer cells. This effect was transcriptional in PC3 and DU145 cells, with p21 mRNA levels increasing in response to NDRG1 expression in a p53-independent manner. The mechanisms involved in this effect may involve the p63 isoform Np63 and also a 60kDa MDM2 isoform, both of which are affected by NDRG1 in these cells and are able to modulate p21 expression. Further studies in PaCa have identified that NDRG1 is able to modulate the TGF-β pathway in this disease. Advanced PaCa is often associated with a deregulated TGF-β pathway leading to increased proliferation. We have found that the over-expression of NDRG1 in PaCa may restore normal TGF-β signaling, leading to reduced cell proliferation. In light of these results, our novel iron chelators Bp4eT and Dp44mT, both of which up-regulate NDRG1 in PaCa, were compared to gemcitabine, the current “gold standard” treatment for this disease. Our results show that both Bp4eT and Dp44mT were significantly more active against PaCa compared to gemcitabine in vitro, with & ,000-fold increase in activity in some cell lines. These data reveal for the first time the mechanisms behind the anti-tumor effects of NDRG1 in cancer cells. Furthermore, we have identified novel and potent anti-cancer agents which selectively target this important metastasis suppressor and have promising activity against PaCa. Citation Information: Mol Cancer Ther 2009 (12 Suppl):B172.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.BBAMCR.2008.05.016
Abstract: A recently identified metastasis suppressor, N-myc downstream regulated gene-1 (Ndrg-1), has been shown to reduce the invasion and metastasis of breast, colon, prostate and pancreatic cancer. Among its many functions, Ndrg-1 is involved in modulating differentiation, proliferation and angiogenesis. However, knowledge of the molecular targets of Ndrg-1 is limited. The current study has focused on examining the functions of Ndrg-1 in a number of different cancer cell models including prostate, colon, lung and pancreatic cancer to elucidate the known pleiotropic nature of this protein. Furthermore, the potential gene targets of Ndrg-1 were analyzed using whole genome gene array revealing a substantial number of genes whose expression was affected by this metastasis suppressor. Significantly, Ndrg-1 up-regulated thiamine triphosphatase (Thtpa) expression in three of the four cell models. Thtpa is known to decrease the levels of the energy currency molecule, thiamine triphosphate, suggesting a potential pathway for the anti-proliferative effects of Ndrg-1. Furthermore, Ndrg-1 reduced the protein levels of cathepsin C which plays a role in invasion, indicating a potential mechanism of its anti-metastatic role in pancreatic cancer cells. These findings provide a potential link between the observed functions of Ndrg-1 and its molecular targets, further demonstrating its anti-metastatic effect.
Publisher: Elsevier BV
Date: 03-2019
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 16-10-2012
Abstract: Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 2018
DOI: 10.1158/1535-7163.TARG-17-A165
Abstract: Introduction: The novel thiosemicarbazone, Dp44mT, has shown potent anticancer activity against various cancer types. The activity of this agent is, at least in part, mediated by its ability to upregulate the growth and metastasis suppressor, N-myc Downstream Regulated Gene 1 (NDRG1). NDRG1 inhibits cell proliferation, migration, and invasion by negatively regulating numerous oncogenic signaling pathways. However, the mechanisms by which NDRG1 modulates all these pathways remain to be elucidated. To examine how NDRG1 and Dp44mT affect multiple signalling pathways, we assessed their effects on the ErbB-family of receptor tyrosine kinases, namely epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), as these molecules are key regulators of downstream oncogenic signaling. Methods: PANC1 pancreatic and HT-29 colon human cancer cells were utilized to examine the effects of NDRG1 and Dp44mT on EGFR, HER2, and HER3 levels, localization, and phosphorylation in vitro. PANC1 xenografts were also utilized to examine the effects of Dp44mT on these molecules in vivo. Results: For the first time, we demonstrate that NDRG1 and Dp44mT markedly inhibit the expression, localization, and activation of EGFR, HER2, and HER3. NDRG1 also reduced activation of the MAPK-signalling pathway, which is downstream of the ErbB family of receptors. Further, the anticancer agent, Dp44mT, significantly reduced expression of EGFR, HER2, and HER3 in vivo. Conclusions: This study demonstrates for the first time that the novel thiosemicarbazone, Dp44mT, inhibits the ErbB family of proteins through its upregulation of NDRG1, providing an interesting insight into the mechanisms behind its compelling anticancer activity. Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des Richardson. Novel thiosemicarbazone, Dp44mT, promotes NDRG1 to downregulate oncogenic signaling pathways in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2017 Oct 26-30 Philadelphia, PA. Philadelphia (PA): AACR Mol Cancer Ther 2018 (1 Suppl):Abstract nr A165.
Publisher: Oxford University Press (OUP)
Date: 13-05-2013
Abstract: The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, being a promising new target for cancer treatment. However, the precise molecular effects of NDRG1 remain unclear. Herein, we summarize recent advances in understanding the impact of NDRG1 on cancer metastasis with emphasis on its interactions with the key oncogenic nuclear factor-kappaB, phosphatidylinositol-3 kinase hosphorylated AKT/mammalian target of rapamycin and Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. Recent studies demonstrating the inhibitory effects of NDRG1 on the epithelial-mesenchymal transition, a key initial step in metastasis, TGF-β pathway and the Wnt/β-catenin pathway are also described. Furthermore, NDRG1 was also demonstrated to regulate molecular motors in cancer cells, leading to inhibition of F-actin polymerization, stress fiber formation and subsequent reduction of cancer cell migration. Collectively, this review summarizes the underlying molecular mechanisms of the antimetastatic effects of NDRG1 in cancer cells.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BBAMCR.2016.01.026
Abstract: Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BBAMCR.2016.01.025
Abstract: Melanoma has markedly increased worldwide during the past several decades in the Caucasian population and is responsible for 80% of skin cancer deaths. Considering that metastatic melanoma is almost completely resistant to most current therapies and is linked with a poor patient prognosis, it is crucial to further investigate potential molecular targets. Major cell-autonomous drivers in the pathogenesis of this disease include the classical MAPK (i.e., RAS-RAF-MEK-ERK), WNT, and PI3K signaling pathways. These pathways play a major role in defining the progression of melanoma, and some have been the subject of recent pharmacological strategies to treat this belligerent disease. This review describes the latest advances in the understanding of melanoma progression and the major molecular pathways involved. In addition, we discuss the roles of emerging molecular players that are involved in melanoma pathogenesis, including the functional role of the melanoma tumor antigen, p97/MFI2 (melanotransferrin).
Publisher: American Association for Cancer Research (AACR)
Date: 2018
DOI: 10.1158/1535-7163.TARG-17-B212
Abstract: Iron is critical for cellular proliferation and its depletion leads to a suppression of both DNA synthesis and global translation. These observations suggest that iron depletion may trigger a cellular “stress response.” A canonical response of cells to stress is the formation of stress granules, which are dynamic cytoplasmic aggregates containing stalled preinitiation complexes that function as mRNA triage centers. By differentially prioritizing mRNA translation, stress granules allow for the continued and selective translation of stress response proteins. Although the multi-subunit eukaryotic initiation factor 3 (eIF3) is required for translation initiation, its largest subunit, eIF3a, may not be essential for this activity. Instead, eIF3a is a vital constituent of stress granules and appears to act, in part, by differentially regulating specific mRNAs during iron depletion. Considering this, we investigated eIF3a’s role in modulating iron-regulated genes roteins that are critically involved in proliferation and metastasis. In this study, eIF3a was downregulated and recruited into stress granules by iron depletion as well as by the classical stress inducers, hypoxia and tunicamycin. Iron depletion also increased expression of the metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), and a known downstream repressed target of eIF3a, namely the cyclin-dependent kinase inhibitor, p27kip1. To determine if eIF3a regulates NDRG1 expression, eIF3a was inducibly overexpressed or ablated. Importantly, eIF3a positively regulated NDRG1 expression and negatively regulated p27kip1 expression during iron depletion. This activity of eIF3a could be due to its recruitment to stress granules and/or its ability to differentially regulate mRNA translation during cellular stress. Additionally, eIF3a positively regulated proliferation, but negatively regulated cell motility and invasion, which may be due to the eIF3a-dependent changes in expression of NDRG1 and p27kip1 observed under these conditions. Citation Format: Jasmina Paluncic, Darius J. R. Lane, Federica Saletta, Yohan S. Rahmanto, Zaklina Kovacevic, Des R. Richardson. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2017 Oct 26-30 Philadelphia, PA. Philadelphia (PA): AACR Mol Cancer Ther 2018 (1 Suppl):Abstract nr B212.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 30-06-2011
Abstract: Pancreatic cancer is an aggressive neoplasm, with a mortality rate close to 100%. The most successful agent for pancreatic cancer treatment is gemcitabine, although the overall effect in terms of patient survival remains very poor. This study was initiated to evaluate a novel class of anticancer agents against pancreatic cancer. This group of compounds belongs to the dipyridyl thiosemicarbazone class that have been shown to have potent and selective activity against a range of different neoplasms in vitro and in vivo. We demonstrate for the first time in pancreatic cancer that these agents increase the expression of the growth and metastasis suppressor N-myc downstream-regulated gene 1 and its phosphorylation at Ser330 and Thr346 that is important for its activity against this tumor. In addition, these agents increased expression of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1), whereas decreasing cyclin D1 in pancreatic cancer cells. Together, these molecular alterations account, in part, for the pronounced antitumor activity observed. Indeed, these agents had significantly higher antiproliferative activity in vitro than the established treatments for pancreatic cancer, namely gemcitabine and 5-fluorouracil. Studies in vivo demonstrated that a novel thiosemicarbazone, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride, completely inhibited the growth of pancreatic cancer xenografts with no evidence of marked alterations in normal tissue histology. Together, our studies have identified molecular effectors of a novel and potent antitumor agent that could be useful for pancreatic cancer treatment.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BBADIS.2018.04.011
Abstract: The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), exhibits pleiotropic activity, inhibiting metastasis of various tumor-types, while being correlated with metastasis in others. Notably, NDRG1 phosphorylation and cleavage are associated with its function, although it is unclear if these modifications occur universally, or selectively, in different cancer cell-types and if it contributes to its pleiotropy. Considering the suggested DNA repair role of nuclear NDRG1, the effects of the above post-translational modifications on its nuclear localization was examined. Herein, the full-length (FL) and truncated (T) NDRG1 isoforms were detected using a C-terminus-directed antibody, while only the FL isoform was identified using an N-terminus-directed antibody. For the first time, we demonstrate that the expression of the NDRG1 FL and T forms occurs in all cancer cell-types examined, as does its phosphorylation (p-NDRG1) at Ser330 and Thr346. The FL isoform localized highly in the nucleus compared to the T isoform. Moreover, p-NDRG1 (Ser330) was also markedly localized in the nucleus, while p-NDRG1 (Thr346) was predominantly cytoplasmic in all cell-types. These results indicate the N-terminus region and phosphorylation at Ser330 could be crucial for NDRG1 nuclear localization and function. PTEN silencing indicated that p-NDRG1 (Thr346) could be regulated differentially in different tumor cell-types, indicating PTEN may be involved in the mechanism(s) underlying the pleiotropic activity of NDRG1. Finally, therapeutics of the di-2-pyridylketone thiosemicarbazone class increased nuclear NDRG1 isoforms (FL and T) detected by the C-terminus-directed antibody in HepG2 cells, while having no significant effect in PC3 cells, indicating differential activity depending on the cell-type.
Publisher: Future Science Ltd
Date: 12-2011
DOI: 10.4155/FMC.11.154
Abstract: The response of cells to cellular iron depletion is complex with multiple molecules and signaling pathways being involved. Indeed, this is far broader than just the effect on the classical target, ribonucleotide reductase. It is likely that a network of interactions exists between the molecular players and that the relationships currently known only represent the ‘tip of an iceberg’ in terms of understanding the response of cells to iron deprivation. This article describes some of the research being undertaken in this area by the Richardson group at the University of Sydney, Australia.
Publisher: Impact Journals, LLC
Date: 10-04-2015
Abstract: N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.
Publisher: American Chemical Society (ACS)
Date: 14-07-2009
DOI: 10.1021/JM900552R
Publisher: Portland Press Ltd.
Date: 23-12-2009
DOI: 10.1042/BJ20081610
Abstract: A key to the development of improved pharmacological treatment strategies for cancer is an understanding of the integration of biochemical pathways involved in both tumorigenesis and cancer suppression. Furthermore, genetic markers that may predict the outcome of targeted pharmacological intervention in an in idual are central to patient-focused treatment regimens rather than the traditional ‘one size fits all’ approach. Prostate cancer is a highly heterogenous disease in which a patient-tailored care program is a holy grail. This review will describe the evidence that demonstrates the integration of three established pathways: the tumour-suppressive TGF-β (transforming growth factor-β) pathway, the tumorigenic PI3K/Akt (phosphoinositide 3-kinase rotein kinase B) pathway and the tumour-suppressive PTEN (phosphatase and tensin homologue deleted on chromosome 10) pathway. It will discuss gene polymorphisms and somatic mutations in relevant genes and highlight novel pharmaceutical agents that target key points in these integrated pathways.
Publisher: OMICS Publishing Group
Date: 2012
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.BMC.2010.02.025
Abstract: A group of styrylazanaphthalenes and azanaphthalenediones were synthesized and tested for their anti-proliferative activity. Most of the compounds were obtained with the use of microwave-assisted synthesis. The lipophilicity of the compounds was measured by RP-HPLC and their anti-proliferative activity was assayed against the human SK-N-MC neuroepithelioma and HCT116 human colon carcinoma cell lines. Active compounds were also tested in clonogenity and comet assays. Several quinazolinone and styrylquinazoline analogues were found to have markedly greater anti-proliferative activity than desferoxamine and cis-platin.
Publisher: Bentham Science Publishers Ltd.
Date: 07-2010
DOI: 10.2174/156720110791560991
Abstract: Targeting essential nutrients (eg., those required for DNA synthesis) to inhibit cancer cell growth is a well established therapeutic strategy. A good ex le is the highly successful folate antagonist, methotrexate. However, up until recently, strategies to target iron which is also crucial for DNA synthesis have not been systematically explored to develop agents for the treatment of cancer. Over the last 15 years, our laboratory has embarked upon structure-activity studies designed to develop novel Fe chelators with anti-cancer efficacy. These studies have led to the development of the dipyridyl thiosemicarbazone chelators that show potent and selective anti-cancer activity and which overcome resistance to other cytotoxic agents. This class of compounds include the chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which at optimal doses markedly inhibits tumour growth and is well tolerated. Moreover, this ligand does not induce overt Fe-depletion in vivo, probably because very low doses (0.4 mg/kg) are effective at inhibiting tumour growth. Importantly, our compounds are far more active and less toxic than the chelator, Triapine®, that is being assessed in a wide variety of international clinical trials. A vital part of the mechanism of action of these compounds is their ability to form a redox-active Fe complex that generates radicals to inhibit tumour growth. Due to their relatively high lipophilicity and low molecular weight of this class of compounds, oral activity may be expected in addition to their well known efficacy via the intravenous route.
Publisher: Wiley
Date: 12-02-2020
DOI: 10.1111/BPH.14985
Start Date: 2009
End Date: 2010
Funder: University of Sydney
View Funded ActivityStart Date: 2007
End Date: 2010
Funder: Cancer Institute NSW
View Funded ActivityStart Date: 2018
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2016
Funder: Ramaciotti Foundations
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2007
End Date: 2010
Funder: Australian Rotary Health
View Funded ActivityStart Date: 2015
End Date: 2016
Funder: Cure Cancer Australia Foundation
View Funded ActivityStart Date: 2011
End Date: 2012
Funder: University of Sydney
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: Cancer Institute NSW
View Funded ActivityStart Date: 2013
End Date: 2016
Funder: Cancer Institute NSW
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: Cancer Institute NSW
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Cancer Australia
View Funded Activity