A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel.

Abstract

Chemoresistance of cancer stem cells (CSCs) is considered a major cause of post-treatment recurrence that negatively impacts the prognosis of patients with ovarian cancer. Using CSCs derived from two different ovarian cancer cell lines, we searched for molecules implicated in the chemoresistance of ovarian CSCs and also drugs with which to target those molecules. Knockdown of survivin overexpressed in ovarian CSCs resulted in increased sensitivity to paclitaxel. Treatment at clinically relevant concentrations with CEP-1347, a mixed lineage kinase inhibitor with a known safety profile in humans, reduced survivin expression in ovarian CSCs and sensitized them to paclitaxel. Survivin overexpression plays a key role in the chemoresistance of ovarian CSCs. Introduction of CEP-1347, which targets survivin expression in ovarian CSCs, as a chemosensitizer for conventional ovarian cancer chemotherapy may serve as a rational and feasible approach for better management of ovarian cancer.