Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

中文翻译：

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使用复合物 I 抑制剂二甲双胍和 IACS-010759 靶向癌症和免疫细胞代谢

二甲双胍和 IACS-010759 是两种不同的抗代谢药物。二甲双胍是一种成熟的抗糖尿病药物，可轻度抑制线粒体复合物 I，而 IACS-010759 是一种新型强效线粒体复合物 I 抑制剂。线粒体通过氧化磷酸化 (OXPHOS) 提供三磷酸腺苷，在细胞能量代谢中发挥关键作用。因此，当靶向癌细胞时，线粒体代谢和 OXPHOS 就成为一个弱点。这两种药物在多种癌症中都具有良好的抗肿瘤作用，并得到临床前体外和体内研究的支持。我们提供了它们对癌细胞的直接影响及其免疫调节作用的证据。在临床研究中，虽然二甲双胍的观察性流行病学研究令人鼓舞，但实际试验结果并不如预期。然而，IACS-01075 表现出严重的副作用，从而导致代谢转变为糖酵解和乳酸浓度升高。因此，这两种药物的未来前景取决于二甲双胍的预防性临床试验以及 IACS-01075 对正常细胞可能的毒性作用的调查。