Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
Aix Marseille Univ, CNRS, ICR, Marseille, France.
Expert Opin Ther Targets. 2023 Jul-Dec;27(10):939-952. doi: 10.1080/14728222.2023.2261631. Epub 2023 Oct 30.
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy.
Triphenylphosphonium cation (TPP)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies.
TPP-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
靶向线粒体的药物在临床前模型中作为有前途的抗肿瘤治疗方法正在出现。然而，其中一些药物已显示出临床毒性。开发具有增加的治疗指数的靶向线粒体的改良天然化合物和美国食品和药物管理局 (FDA) 批准的药物是一种替代策略。
基于三苯基膦阳离子 (TPP) 的药物由于其增加的负膜电位而选择性地积聚在癌细胞的线粒体中，靶向氧化磷酸化蛋白，抑制线粒体呼吸，并抑制肿瘤增殖。基于 TPP 的药物在啮齿动物和人类中产生最小的毒副作用。这些药物可以增强辐射和免疫疗法的作用。
靶向肿瘤线粒体电子传递链的基于 TPP 的药物是一类新型的氧化磷酸化抑制剂，具有不同的增殖抑制和抗转移潜力。其中一些基于 TPP 的药物是从天然存在的分子和 FDA 批准的药物合成的，已在小鼠中进行了测试，并且在低于最大耐受剂量的剂量下使用时没有表现出明显的毒性，包括神经毒性。因此，应该更加努力地将基于 TPP 的 OXPHOS 抑制剂药物转化为癌症的预防和治疗。
