Targeting mitochondria by anthelmintic drug atovaquone sensitizes renal cell carcinoma to chemotherapy and immunotherapy

Journal of Biochemical and Molecular Toxicology
Dehong ChenJun Cao

Abstract

Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration-dependent and time-dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone-treated cells, atovaquone decreased ATP levels. As a consequence of mitochondrial respiration inhibition, reactive oxygen species levels were increased by atovaquone. The complete rescue of atovaquone's effects by an antioxidant suggests the important role of oxidative stress in the action of atovaquone in RCC. Importantly, atovaquone enhanced the in vitro and in vivo efficacy of 5-fluorouracil (5-FU) and interferon-α (IFN-α). Our preclinical findings suggest that atovaquone is a useful addition for RCC treatment. Our work also further demonstrates that RCC is more dependent on mitochondrial respiration than glycolysis.

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Citations

Jul 17, 2020·International Journal of Molecular Sciences·Federica LaudisiCarmine Stolfi
Oct 9, 2020·Journal of Experimental & Clinical Cancer Research : CR·Faiqa MudassarEric Hau
May 8, 2020·Seminars in Cancer Biology·Anuradha KirtoniaManoj Garg
Oct 27, 2020·Journal of Medicinal Chemistry·Yibin XuNouri Neamati
Jan 10, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Daan F BoreelJohan Bussink
May 18, 2021·Frontiers in Oncology·Yan-Qi LiJi-Gang Dai
Oct 14, 2021·The Journal of International Medical Research·Bo WangChengjun Qiu

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