Atovaquone at clinically relevant concentration overcomes chemoresistance in ovarian cancer via inhibiting mitochondrial respiration

Abstract

The poor outcomes in ovarian cancer necessitate new treatments. Strategies to interfere with oxidative phosphorylation have been recently highlighted for the treatment of ovarian tumors. Atovaquone, an approved antimicrobial drug, has demonstrated anti-cancer potential and ability in disrupting mitochondrial function. Here, we investigated the efficacy of atovaquone as single drug and its combination with cisplatin in ovarian cancer. We show that atovaquone at clinically achievable concentrations is active against ovarian cancer bulky and stem-cell like cells via inhibiting growth and colony formation, and inducing caspase-dependent apoptosis. In contrast, atovaquone either does not or inhibits normal cells in a less extent than in ovarian cancer cells. Mechanism studies using multiple independent approaches demonstrate that atovaquone acts on ovarian cancer cells via decreasing mitochondrial complex III which results in mitochondrial respiration inhibition, energy reduction and oxidative stress. In line with in vitro findings, atovaquone alone at non-toxic dose is effective in inhibiting ovarian cancer growth in vivo, and its combination with cisplatin is synergistic. Our study suggests that atovaquone is a promising candidate to the treatment of ovarian cancer. Our work also supports the notion that mitochondrial respiration is a therapeutic target in ovarian cancer.

Keywords: Atovaquone; Chemoresistance; Mitochondrial dysfunction; Oxidative stress.