Clotrimazole Targets the c-Myc-Survivin Axis to Reduce the Viability of Ovarian Cancer Stem Cells Alone and in Combination with Chemotherapeutic Agents.

Ovarian cancer stem cells (OvCSCs) are one of the main factors contributing to post-treatment recurrence and the poor prognosis of patients with ovarian cancer. Therefore, the development of therapeutic strategies targeting OvCSCs is needed to improve patient survival. We previously reported the high expression of survivin/BIRC5 in OvCSCs and also that targeting pathways regulating survivin expression effectively suppressed OvCSC survival. In the present study, we tested a panel of agents consisting of FDA-approved drugs and compounds under clinical studies for their ability to suppress survivin expression in OvCSCs and identified clotrimazole (CTZ) as a potent candidate. The effects of CTZ on survivin expression were examined by RT-PCR and Western blot analyses. The effects of CTZ alone or in combination with anticancer agents on OvCSCs were evaluated using WST-8, PI uptake, and colony formation assays. CTZ preferentially impaired OvCSC survival by suppressing the c-myc-survivin axis without affecting normal fibroblasts and enhanced the efficacy of platinum- and taxane-based chemotherapeutic agents. These results suggest that CTZ suppresses survivin expression in OvCSCs and enhances the effects of conventional ovarian cancer chemotherapeutic agents, supporting further investigations of this approach as a potential strategy for ovarian cancer treatment.