ORCID Profile
0000-0001-7755-0826
Current Organisations
UCSF Helen Diller Family Comprehensive Cancer Center
,
University of Queensland
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Publisher: Elsevier BV
Date: 04-2021
DOI: 10.1016/J.NEUROPHARM.2021.108503
Abstract: Beyond abnormalities in the neurotransmitter hypothesis, recent evidence suggests that mitochondrial dysfunction and immune-inflammatory responses contribute to the pathophysiology of schizophrenia. The prefrontal cortex (PFC) undergoes maturation and development during adolescence, which is a critical time window in life that is vulnerable to environmental adversities and the development of psychiatric disorders such as schizophrenia. Applying eight weeks of post-weaning social isolation stress (PWSI) to rats, as an animal model of schizophrenia, we decided to investigate the effects of PWSI on the mitochondrial function and expression of immune-inflammatory genes in the PFC of normal and stressed rats. To do this, control and PWSI rats were ided into treatment (clozapine CLZ, 2.5 mg/kg/day for 28 days) and non-treatment sub-groups. Our results showed PWSI caused schizophrenic-like behaviors in rats and induced mitochondrial dysfunction as well as upregulation of genes associated with innate immunity in the PFC. Chronic treatment with CLZ attenuated the effects of PWSI on behavioral abnormalities, mitochondrial dysfunction, and immune-inflammatory responses in the PFC of rats. These results may advance our understanding about the mechanism of action of CLZ that targets mitochondrial dysfunction and immune-inflammatory responses as factors involved in the pathophysiology of schizophrenia.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-04-2021
DOI: 10.1126/SCITRANSLMED.ABE2967
Abstract: The phosphorylation status of oncoproteins is regulated by both kinases and phosphatases. Kinase inhibitors are rarely sufficient for successful cancer treatment, and phosphatases have been considered undruggable targets for cancer drug development. However, innovative pharmacological approaches for targeting phosphatases have recently emerged. Here, we review progress in the therapeutic targeting of oncogenic Src homology region 2 domain-containing phosphatase-2 (SHP2) and tumor suppressor protein phosphatase 2A (PP2A) and select other druggable oncogenic and tumor suppressor phosphatases. We describe the modes of action for currently available small molecules that target phosphatases, their use in drug combinations, and advances in clinical development toward future cancer therapies.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.EJPHAR.2021.174404
Abstract: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with the highest mortality rate and a poor 5-year survival rate. The majority of the cases are diagnosed in advanced stages when the disease has spread, which makes the tumor inoperable. Due to the antigenic essence of lung tumor cells, immunotherapy is a novel area and has exhibited remarkable results in this malignancy. Immune checkpoint inhibitors are inhibitory molecules that disrupt immune checkpoint signaling pathways whether in the immune cells or tumor cells. Tremelimumab and ipilimumab (CTLA-4 blockers), pembrolizumab and nivolumab (PD-1 blockers), and durvalumab, avelumab, and atezolizumab (PD-L1 blockers) are FDA-approved and improve the survival and objective response of NSCLC patients. Despite this, over-stimulation of the immune system via the immune checkpoint therapy is a double-edged sword that causes a spectrum of adverse events from moderate to life-threatening. Nanomedicine considerably impacts the way of diagnosis and treatment of tumors to overcome treatment-related challenges. Accordingly, nanoparticle-based immune checkpoint inhibitor therapy increases the local concentration of immune checkpoint inhibitors while reduces the side effects, which result in boosting the anti-tumor immunity against various types of malignancies, including NSCLC. The current review provides comprehensive information about immune checkpoint therapy in NSCLC, their efficacy, and their safety profile. Besides, recent advances in nanoparticle-based immune checkpoint therapy and its limitation are discussed.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2019
DOI: 10.1007/S13402-019-00448-W
Abstract: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-07-2018
DOI: 10.1126/SCITRANSLMED.AAQ1093
Abstract: Pharmacological PP2A activation is a druggable approach to overcome MEK inhibitor resistance.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2020
DOI: 10.1007/S13402-019-00473-9
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells. Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib. We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail. Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.
Publisher: Informa UK Limited
Date: 12-2022
DOI: 10.1080/10799893.2020.1853159
Abstract: The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.
Location: United States of America
No related grants have been discovered for Majid Momeny.