BackgroundNumerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy. In this study, we investigated the effects of BAY 87-2243, a small molecule that inhibits the first OXPHOS enzyme (complex I), in melanoma in vitro and in vivo.ResultsBAY 87-2243 decreased mitochondrial oxygen consumption and induced partial depolarization of the mitochondrial membrane potential. This was associated with increased reactive oxygen species (ROS) levels, lowering of total cellular ATP levels, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The latter was rescued by the antioxidant vitamin E and high extracellular glucose levels (25 mM), indicating the involvement of ROS-induced cell death and a dependence on glycolysis for cell survival upon BAY 87-2243 treatment. BAY 87-2243 significantly reduced tumor growth in various BRAF mutant melanoma mouse xenografts and patient-derived melanoma mouse models. Furthermore, we provide evidence that inhibition of mutated BRAF using the specific small molecule inhibitor vemurafenib increased the OXPHOS dependency of BRAF mutant melanoma cells. As a consequence, the combination of both inhibitors augmented the anti-tumor effect of BAY 87-2243 in a BRAF mutant melanoma mouse xenograft model.ConclusionsTaken together, our results suggest that complex I inhibition has potential clinical applications as a single agent in melanoma and also might be efficacious in combination with BRAF inhibitors in the treatment of patients with BRAF mutant melanoma.

中文翻译：

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使用 BAY 87-2243 靶向线粒体复合物 I 可减少黑色素瘤肿瘤的生长

背景大量研究表明，功能性线粒体是肿瘤发生所必需的，这表明线粒体氧化磷酸化 (OXPHOS) 可能是癌症治疗的潜在靶点。在这项研究中，我们研究了 BAY 87-2243（一种抑制第一种 OXPHOS 酶（复合物 I）的小分子）在体外和体内黑色素瘤中的作用。结果 BAY 87-2243 降低线粒体耗氧量并诱导部分去极化线粒体膜电位。这与活性氧 (ROS) 水平增加、细胞总 ATP 水平降低、AMP 活化蛋白激酶 (AMPK) 激活和细胞活力降低有关。后者被抗氧化维生素 E 和高细胞外葡萄糖水平 (25 mM) 拯救，表明 ROS 诱导的细胞死亡的参与以及 BAY 87-2243 处理后细胞存活依赖于糖酵解。BAY 87-2243 显着降低了各种 BRAF 突变黑色素瘤小鼠异种移植物和患者来源的黑色素瘤小鼠模型中的肿瘤生长。此外，我们提供的证据表明，使用特定的小分子抑制剂威罗菲尼抑制突变的 BRAF 会增加 BRAF 突变黑色素瘤细胞的 OXPHOS 依赖性。因此，两种抑制剂的组合增强了 BAY 87-2243 在 BRAF 突变黑色素瘤小鼠异种移植模型中的抗肿瘤作用。