Presentation Title

Enhancement of MDM2 Inhibitory Effects through Blocking Mechanisms in A2780 ovarian cancer cells

Presenter(s)

Amal AlzahraniFollow

Presenter Credentials

Amal Alzahrani, Pharmaceutical Sciences, College of Pharmacy, fourth year, Ph.D.

Presenter Degree

Ph.D.

Co-Author Credentials

Umamaheswari Natarajan, Ph.D., Research Associate, Rumbaugh-Goodwin Institute for Cancer Research. Appu Rathinavelu, Ph.D., Professor and Executive Director, Rumbaugh-Goodwin Institute for Cancer Research, College of Pharmacy, Nova Southeastern University

College

College of Pharmacy

Campus Location

Ft. Lauderdale

Format

Poster

IRB Approval Verification

N/A

Abstract

Objective. The study was conducted to assess the efficacy of RG-7388 in combination with Selinexor in an ovarian cancer cell line (A2780). Background. Ovarian cancer is a gynecological disease responsible for about 5% of cancer deaths among women. It is confirmed that ovarian cancer develops to metastatic type with a higher mortality rate in 75% of patients compared to other cancer types. Although abundant research efforts have been made to find optimum treatments for ovarian cancer over the last decades, patients are still facing frequent relapses and the development of chemotherapy resistance. Several studies have shown that p53 mutations or inactivation is one of the early events during the development of ovarian cancer and contribute to both metastatic progression and chemoresistance. In this study, we attempted to exploit the molecular alteration of p53 to develop a new treatment strategy for ovarian cancer by combining the MDM2 inhibitor (RG-7388) with Selective inhibitor of nuclear export (Selinexor). Methods. For this study, MTT assay was conducted with A2780 cells that were treated with RG-7388, Selinexor, and combination of them at different concentrations for 24h. Western Blotting analysis was conducted to assess the expression levels of MDM2, p53, phospho-p53, and p21 proteins. Microscopic images obtained with DEVD-amc fluorogenic substrates was applied to determine the apoptotic effects of RG-7388 and Selinexor. Results. Combination of RG-7388 (1µM) and Selinexor (1µM) was able to reduce the cell viability by 50% after 24 h compared to individual treatments of (2µM) RG-7388 and (2µM) Selinexor. Moreover, the combination of RG-7388 and Selinexor revealed significant up-regulation of MDM2, p53, phospho-p53, and p21 in whole lysate, cytosol, and nucleus. Finally, the cells treated with the drug combination produced high levels of fluorescence compared to individual treatments, which indicated high levels of apoptosis. Conclusion. Our results confirmed that the combination of RG-7388 (1µM) and Selinexor (1µM) is able to reduce the viability of ovarian cancer cells, through up-regulation of MDM2, p53, phospho-p53, and p21, and induction of caspase mediated apoptotic mechanism. Grants. The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida, funded this study.

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Enhancement of MDM2 Inhibitory Effects through Blocking Mechanisms in A2780 ovarian cancer cells

Objective. The study was conducted to assess the efficacy of RG-7388 in combination with Selinexor in an ovarian cancer cell line (A2780). Background. Ovarian cancer is a gynecological disease responsible for about 5% of cancer deaths among women. It is confirmed that ovarian cancer develops to metastatic type with a higher mortality rate in 75% of patients compared to other cancer types. Although abundant research efforts have been made to find optimum treatments for ovarian cancer over the last decades, patients are still facing frequent relapses and the development of chemotherapy resistance. Several studies have shown that p53 mutations or inactivation is one of the early events during the development of ovarian cancer and contribute to both metastatic progression and chemoresistance. In this study, we attempted to exploit the molecular alteration of p53 to develop a new treatment strategy for ovarian cancer by combining the MDM2 inhibitor (RG-7388) with Selective inhibitor of nuclear export (Selinexor). Methods. For this study, MTT assay was conducted with A2780 cells that were treated with RG-7388, Selinexor, and combination of them at different concentrations for 24h. Western Blotting analysis was conducted to assess the expression levels of MDM2, p53, phospho-p53, and p21 proteins. Microscopic images obtained with DEVD-amc fluorogenic substrates was applied to determine the apoptotic effects of RG-7388 and Selinexor. Results. Combination of RG-7388 (1µM) and Selinexor (1µM) was able to reduce the cell viability by 50% after 24 h compared to individual treatments of (2µM) RG-7388 and (2µM) Selinexor. Moreover, the combination of RG-7388 and Selinexor revealed significant up-regulation of MDM2, p53, phospho-p53, and p21 in whole lysate, cytosol, and nucleus. Finally, the cells treated with the drug combination produced high levels of fluorescence compared to individual treatments, which indicated high levels of apoptosis. Conclusion. Our results confirmed that the combination of RG-7388 (1µM) and Selinexor (1µM) is able to reduce the viability of ovarian cancer cells, through up-regulation of MDM2, p53, phospho-p53, and p21, and induction of caspase mediated apoptotic mechanism. Grants. The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida, funded this study.