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Induction of apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. The purpose of this study was to determine whether Indole-3-Carbinol (I3C) and Genistein in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis in endometrial cancer cell (Ishikawa) and to assess apoptotic mechanism. The MTT assay and flow cytometry were performed to determine cell viability and cell cycle. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay, annexin V binding assay and western blot analysis. There was no effect in cell growth inhibition and cell cycle progression alone or in two-combination. However, the treatment of I3C and Genistein followed by TRAIL showed significant cell death and marked increase in sub-G1 arrest. Three-combination treatment revealed elevated expression of DR4, DR5 and cleaved forms of caspase-3, caspase-8, PARP. The Flip was found down regulated. Moreover, increase in caspase-3 activity and DNA fragmentation indicated the induction of apoptosis. The results indicate that I3C and Genistein with TRAIL synergistically induced apoptosis via death receptor dependent pathway. Our findings might provide a new insight into the development of novel combination therapies against endometrial cancer.

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Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world. Drug resistance is the main cause of treatment failure and mortality in cancer patients. The objective of this study was to establish a paclitaxel (PTX)-resistant human ovarian carcinoma cell line (OVCAR3) and to sensitize chemoresistant cells. The drug-resistant tumor cell lines were established in vitro by stepwise sequential exposure to increased concentration of PTX. For sensitization, OVCAR3/PTX cells were treated with different concentration of salinomycin alone or combined with PTX. The cell viability and cell cycle distribution was measured by MTT and flow cytometric analysis. The transcriptional change of mRNA was examined by RT-PCR. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay and western blot analysis. The cell viability was significantly reduced by combination treatment in a dose dependent manner. The flow cytometry result showed an increase in sub-G1 phase. Combination treatment enhanced the sensitivity of OVCAR3/PTX cells to PTX with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, we demonstrated potential effect of salinomycin in sensitization of PTX resistant ovarian tumor growth. Our results suggest salinomycin in combination with PTX may be a beneficial chemotherapeutic strategy, especially in patients with tumors refractory to PTX alone. Citation Format: Chi-Heum Cho, Hyun-Gyo Lee, Bidur Parajuli, So-Jin Shin, Sang-Hoon Kwon, Soon-Do Cha. Salinomycin sensitized paclitaxel-resistant human ovarian cancer cells and induced apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 973. doi:10.1158/1538-7445.AM2013-973