Targeting ATP Synthase by Bedaquiline as a Therapeutic Strategy to Sensitize Ovarian Cancer to Cisplatin

Cisplatin is a common chemotherapeutic drug for treating ovarian cancer, but its clinical efficacy is hampered by intrinsic and acquired resistance. Previous studies had shown inhibiting oxidative phosphorylation overcomes cisplatin resistance in ovarian cancer. Studies reveal that bedaquiline, a clinically available antimicrobial drug, inhibits cancer via targeting mitochondria. This study systematically assessed the efficacy of bedaquiline in ovarian cancer and its underlying mechanism. Using a panel of ovarian cancer cell lines and normal ovary cells, we demonstrated bedaquiline is selective for anti-ovarian cancer activities. Furthermore, the sensitivity varied among different ovarian cancer cell lines regardless of their sensitivity to cisplatin. Bedaquiline inhibited growth, survival and migration, through decreasing levels of ATP synthase subunit, complex V activity, mitochondrial respiration and ATP. We further found that ovarian cancer displayed increased levels of ATP, oxygen consumption rate (OCR), complex V activity and ATP synthase subunits compared to normal counterpart. Combination index analysis showed that bedaquiline and cisplatin is synergistic. Bedaquiline remarkably enhanced the efficacy of cisplatin in inhibiting ovarian cancer growth in mice. Our study provides evidence to repurpose bedaquiline for ovarian cancer treatment and suggests that ATP synthase is a selective target to overcome cisplatin resistance in ovarian cancer.