Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Nat Commun. 2021 Jun 3;12(1):3299. doi: 10.1038/s41467-021-23396-2.
Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.
生物能量学的改变导致肿瘤生长增加活性氧（ROS）的产生，需要增加 ROS 清除剂来限制氧化应激。因此，同时诱导能量和氧化应激的干预策略具有治疗潜力。苯乙双胍是一种线粒体复合物 I 抑制剂，可诱导生物能量学应激。我们现在证明，炎性介质，包括 IFNγ 和 polyIC，通过 STAT1 依赖性机制诱导氧化应激的平行增加，从而增强苯乙双胍的细胞毒性。事实上，STAT1 信号通路在许多乳腺癌模型中下调 NQO1，一种关键的 ROS 清除剂。此外，使用β-拉帕醌（一种 NQO1 可激活的药物）对 NQO1 进行基因敲除或药理学抑制，增加氧化应激，选择性地使包括 HER2+和三阴性疾病的患者来源异种移植在内的乳腺癌模型对苯乙双胍的杀伤作用敏感。我们提供的证据表明，针对 ROS 清除剂的治疗方法可提高乳腺癌中线粒体复合物 I 抑制剂的抗肿瘤疗效。
