Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells

Abstract

Chemotherapy often fails to eradicate cancer stem cells (CSCs) that drive cancer recurrence. In fact, the treated tumors often contain a higher frequency of chemo-resistant CSCs. It is thought that CSC formation is supported by exposure of cancer cells to sub-cytotoxic chemotherapy doses as a result of poor drug penetration in epithelial tumors. We have shown that low-dos cisplatin triggers the transdifferentiation of ovarian cancer cells into CSCs through processes that are also involved in the generation and maintenance of induced pluripotent stem (iPS) cells. Considering similarities between CSCs and iPS cells, we screened a library of 60 synthetic small-molecule compounds, designed to influence EMT/MET signaling in iPS cells on primary ovarian cancer cells. Using a Nanog reporter system we identified a series of compounds capable of blocking the cisplatin triggered formation of CSCs. We then focused on compound GHDM-1515, a drug that acts on pathways that regulate histone demethylases. We demonstrated that co-treatment of primary ovarian cancer cells with GHDM-1515 significantly increased cisplatin induced apoptosis, specifically apoptosis of CSCs. GHDM-1515 inhibited EMT and the cisplatin-induced formation of CSCs. This suggests that GHDM-1515 can sensitize ovarian cancer cells to low-dose cisplatin and potentially enhance the efficacy of cisplatin chemotherapy.