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

2020; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41598-020-74808-0

2045-2322

Gang Cheng, Micaël Hardy, Paytsar Topchyan, Ryan Zander, Peter J. Volberding, Weiguo Cui, Balaraman Kalyanaraman,

Pharmacological Receptor Mechanisms and Effects

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 4 -ATO, Mito 10 -ATO, Mito 12 -ATO, and Mito 16 -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 4 -ATO and Mito 10 -ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito 12 -ATO and Mito 16 -ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.