Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze University, Jingzhou, China.
Department of Pulmonary and Critical Care Medicine, Jingzhou Hospital, Yangtze University, Jingzhou, China.
Eur J Pharmacol. 2021 Sep 15;907:174256. doi: 10.1016/j.ejphar.2021.174256. Epub 2021 Jun 12.
Chemoresistance has been associated with increased reliance on mitochondrial functions in many cancers, including lung cancer. Atovaquone is an anti-malaria drug and mitochondrial inhibitor. In this work, we attempted to explore whether atovaquone can be repurposed for lung cancer treatment to overcome chemoresistance. We showed that atovaquone inhibited proliferation, colony formation and survival in non-small cell lung cancer cell (NSCLC) cells. Of note, the effective dose of atovaquone was clinically achievable. Combination index value indicated that atovaquone and carboplatin were synergistic in inhibiting NSCLC. The potent efficacy of atovaquone and its synergism with chemotherapeutic drug were also demonstrated in NSCLC xenograft mice model. Mechanism studies showed that the synergism between atovaquone and carboplatin was due to atovaquone's ability in disrupting mitochondrial functions via specifically inhibiting complex III induced oxygen consumption. Subsequently, atovaquone activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR) signaling. AMPK inhibition reversed the anti-NSCLC activity of atovaquone, suggesting that the action of atovaquone is also dependent on AMPK. Our work suggests that atovaquone is an attractive candidate for NSCLC treatment. Our findings emphasize that inhibition of mitochondrial function is a promising therapeutic strategy to enhance NSCLC chemosensitivity.
耐药性与许多癌症（包括肺癌）中线粒体功能的依赖增加有关。阿托伐醌是一种抗疟疾药物和线粒体抑制剂。在这项工作中，我们试图探索阿托伐醌是否可以被重新用于肺癌治疗以克服耐药性。我们表明，阿托伐醌抑制非小细胞肺癌（NSCLC）细胞的增殖、集落形成和存活。值得注意的是，阿托伐醌的有效剂量在临床是可达到的。组合指数值表明，阿托伐醌和卡铂在抑制 NSCLC 方面具有协同作用。阿托伐醌在 NSCLC 异种移植小鼠模型中的强大疗效及其与化疗药物的协同作用也得到了证明。机制研究表明，阿托伐醌与卡铂的协同作用是由于阿托伐醌通过特异性抑制复合物 III 诱导的耗氧量来破坏线粒体功能的能力。随后，阿托伐醌激活 AMP 激活的蛋白激酶（AMPK）并抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号。AMPK 抑制逆转了阿托伐醌对 NSCLC 的抗癌活性，表明阿托伐醌的作用也依赖于 AMPK。我们的工作表明，阿托伐醌是治疗 NSCLC 的有吸引力的候选药物。我们的研究结果强调，抑制线粒体功能是增强 NSCLC 化疗敏感性的有前途的治疗策略。
