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

Abstract

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.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Ethics Approval and Consent to Participate

All animal studies were approved by Institutional Animal Care and Use Committee of Hubei University of Medicine.

Author Contributions

HYZ and QTC conducted the experiments, performed analysis, and wrote the manuscript. LLZ and PCH supervised the project, analyzed the data, and edited the manuscript. All authors approved the manuscript.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by a research grant provided by Hubei Provincial Natural Science Foundation of China (2021CFB582), Health Commission of Hubei Provincial scientific research project (WJ2021M069), Educational Commission of Hubei Province scientific research project (D20212103) and the Science and Technology Development Project of Xiangyang (2021YL23).