Salinomycin induces apoptosis via death receptor-5 up-regulation in cisplatin-resistant ovarian cancer cells.

Background: Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to effective disease treatment. Recently, salinomycin was proven to be highly-effective for the elimination of cancer stem cells both in vitro and in vivo. The objective of the present study was to evaluate the anticancer properties of salinomycin in cisplatin-resistant ovarian cancer cells (A2780cis). Materials and Methods: The tetrazolium dye (MT7') assay was used to determine cell viability. Flow cytometric analysis was performed to analyze the effect on cell cycle and apoptosis. The expression of apoptosis-related proteins was evaluated by western blot analysis. Results: Cell viability was significantly reduced by salinomycin treatment in a dose-dependent manner. Flow cytometry showed an increase in sub-G(1) phase cells. Salinomycin increased the expression of death receptor-5 (DR5), caspase-8 and Fas-associated protein with death domain (FADD). A decline in the expression of FLICE-like inhibitory protein (FLIP), activation of caspase-3 and increased poly ADP-ribose polymerase (PARP) cleavage, triggered apoptosis. Furthermore, annexin-V staining also revealed the apoptotic induction. Conclusion: These findings provide important insights regarding the activation of caspase-8 and DR5, to our knowledge, for the first time in salinomycin-treated cisplatin-resistant ovarian cancer and demonstrate that salinomycin could be a prominent anticancer agent.