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

J Biochem Mol Toxicol. 2018 Sep;32(9):e22195. doi: 10.1002/jbt.22195. Epub 2018 Jul 13.

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.

Keywords: atovaquone; complex III; drug combination; mitochondria; renal cancer.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anthelmintics / chemistry
  • Anthelmintics / pharmacology
  • Antimetabolites, Antineoplastic / chemistry
  • Antimetabolites, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Atovaquone / antagonists & inhibitors
  • Atovaquone / pharmacology*
  • Atovaquone / therapeutic use
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Electron Transport Complex III / antagonists & inhibitors*
  • Electron Transport Complex III / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Interferon-alpha / agonists
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Male
  • Mice, SCID
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects
  • Random Allocation
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Anthelmintics
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Antioxidants
  • Enzyme Inhibitors
  • Interferon-alpha
  • Electron Transport Complex III
  • Atovaquone