Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines.

Cisplatin derivatives are used as the mainline treatment of ovarian cancer, despite their severe side effects and development of resistance. We developed a novel combination therapy by combining cisplatin with withaferin A. Treatment of ovarian cancer cell lines with combination therapy acted synergistically to induce cell death, thus required a lower dose of cisplatin to achieve the same therapeutic effect. WFA and cisplatin combination induced cell death through the generation of reactive oxygen species (ROS) for WFA, while DNA damage for cisplatin, suggesting that cisplatin binds directly to DNA to form adducts while WFA indirectly damages DNA through ROS generation. Our results for the first time suggest that combining low dose of cisplatin with suboptimal dose of WFA can serve as a potential combination therapy for the treatment of ovarian cancer with the potential to minimize/eliminate the side effects associated with high doses of cisplatin.