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Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone. Sci Rep 2020 Oct 21;10(1):17872

Date

10/23/2020

Pubmed ID

33087770

Pubmed Central ID

PMC7578061

DOI

10.1038/s41598-020-74808-0

Scopus ID

2-s2.0-85093870747 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

The FDA-approved prophylactic antimalarial drug atovaquone (ATO) recently was repurposed as an antitumor drug. Studies show that ATO exerts a profound antiproliferative effect in several cancer cells, including breast, ovarian, and glioma. Analogous to the mechanism of action proposed in parasites, ATO inhibits mitochondrial complex III and cell respiration. To enhance the chemotherapeutic efficacy and oxidative phosphorylation inhibition, we developed a mitochondria-targeted triphenylphosphonium-conjugated ATO with varying alkyl side chains (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO). Results show, for the first time, that triphenylphosphonium-conjugated ATO potently enhanced the antiproliferative effect of ATO in cancer cells and, depending upon the alkyl chain length, the molecular target of inhibition changes from mitochondrial complex III to complex I. Mito4-ATO and Mito10-ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito12-ATO and Mito16-ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.

Author List

Cheng G, Hardy M, Topchyan P, Zander R, Volberding P, Cui W, Kalyanaraman B

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antimalarials
Antineoplastic Agents
Apoptosis
Arsenicals
Atovaquone
Cell Line, Tumor
Cell Proliferation
Cell Respiration
Electron Transport Complex I
Electron Transport Complex III
Humans
Mice
Mitochondria
Neoplasms
Organophosphorus Compounds
Oxidative Phosphorylation
Oxides
Oxygen Consumption