Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

Gang Cheng; Micael Hardy; Paytsar Topchyan; Ryan Zander; Peter Volberding; Weiguo Cui; Balaraman Kalyanaraman

doi:10.1038/s41598-020-74808-0

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Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

Journal article

Open access

Peer reviewed

Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

Gang Cheng, Micael Hardy, Paytsar Topchyan, Ryan Zander, Peter Volberding, Weiguo Cui and Balaraman Kalyanaraman

Scientific reports, Vol.10(1), pp.17872-17872

10/21/2020

DOI: 10.1038/s41598-020-74808-0

PMCID: PMC7578061

PMID: 33087770

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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 (Mito -ATO, Mito -ATO, Mito -ATO, and Mito -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. Mito -ATO and Mito -ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito -ATO and Mito -ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.

Animals

Antimalarials - pharmacology

Antineoplastic Agents - metabolism

Antineoplastic Agents - pharmacology

Apoptosis - drug effects

Arsenicals - pharmacology

Atovaquone - chemistry

Atovaquone - metabolism

Atovaquone - pharmacology

Cell Line, Tumor

Cell Proliferation - drug effects

Cell Respiration - drug effects

Electron Transport Complex I - drug effects

Electron Transport Complex III - drug effects

Humans

Mice

Mitochondria - drug effects

Mitochondria - metabolism

Neoplasms - drug therapy

Neoplasms - metabolism

Organophosphorus Compounds - chemistry

Oxidative Phosphorylation

Oxides - pharmacology

Oxygen Consumption - drug effects

Details

Title: Subtitle: Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone
Creators: Gang Cheng - Medical College of Wisconsin
Micael Hardy - Aix-Marseille Université
Paytsar Topchyan - Medical College of Wisconsin
Ryan Zander - Medical College of Wisconsin
Peter Volberding - Medical College of Wisconsin
Weiguo Cui - Medical College of Wisconsin
Balaraman Kalyanaraman - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: Scientific reports, Vol.10(1), pp.17872-17872
DOI: 10.1038/s41598-020-74808-0
PMID: 33087770
PMCID: PMC7578061
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: R01 AI148403 / NIAID NIH HHS F30 CA246920 / NCI NIH HHS CA246920 / NIH HHS AI125741 / NIH HHS R01 AI125741 / NIAID NIH HHS
Language: English
Date published: 10/21/2020
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297434502771

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