Coates James T T, Rodriguez-Berriguete Gonzalo, Puliyadi Rathi, Ashton Thomas, Prevo Remko, Wing Archie, Granata Giovanna, Pirovano Giacomo, McKenna Gillies W, Higgins Geoff S
Department of Oncology, University of Oxford, Oxford, UK.
Cell Death Discov. 2020 Oct 27;6:110. doi: 10.1038/s41420-020-00343-6. eCollection 2020.
Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.
铂类化疗药物是高效的细胞毒性药物，但作为单一疗法使用时常常会诱导耐药性。联合治疗策略可降低这种风险，并为多种癌症提供有效的治疗选择。在此，我们通过证明阿托伐醌（ATQ）能增强铂类药物对一部分癌细胞的杀伤作用，从而将其重新用于癌症治疗。我们发现，ATQ与卡铂或顺铂联合使用时，在多种癌细胞系中均能在体外诱导显著且可重复的浓度和时间依赖性细胞死亡致敏作用。ATQ可诱导线粒体活性氧（mROS），以浓度依赖的方式消耗细胞内谷胱甘肽（GSH）池。超氧化物歧化酶模拟物MnTBAP可挽救ATQ诱导的mROS产生，而用GSH前体药物N - 乙酰半胱氨酸（NAC）预加载细胞可消除致敏作用。这些发现共同表明，ATQ诱导的氧化应激是致敏作用的关键介质。在生理可达到的浓度下，ATQ和卡铂还能协同延缓三维无血管球体的生长。在临床上，ATQ是电子传递链（ETC）的一种安全且特异性的抑制剂，同时正被重新用作候选肿瘤缺氧调节剂。这些发现共同表明，ATQ作为候选铂类致敏剂值得进一步研究。
