Targeting ROS production in OXPHOS-defective and OXPHOS-competent tumors

最近对癌症新陈代谢的研究启发了许多抗癌的新想法 接近了。其中一个很有希望的方法是利用控制活性物质产生的机制。 癌症中的氧物种(ROS)。一些致癌突变和肿瘤缺氧已知增加。 癌细胞产生ROS，可能在促进肿瘤生长和转移中发挥重要作用。 然而，ROS是一把双刃剑，因为过多的ROS也会杀死癌细胞。 实体肿瘤内的癌细胞通常居住在低氧环境中，这意味着氧气水平 远低于正常组织中的含量。尽管如此，大多数抗癌药物都是用癌症发现的。 细胞维持在正常的生理氧气浓度下。在低氧条件下，癌细胞 表现出氧化磷酸化(OXPHOS)缺陷，并经历代谢重新编程。因此， 他们变得更具攻击性，对常用的治疗方法也更具抵抗力。因此，治疗方法是 能否有效消除缺氧性肿瘤是迫切需要的。使用化学筛查，我们已经识别出一种 一种化合物，在低氧条件下对多种癌细胞和癌症具有强烈的细胞毒作用 携带OXPHOS突变的细胞。有趣的是，我们的结果进一步表明，线粒体ROS的激增 细胞毒性的原因，并指出OXPHOS中一种以前未被识别的产生ROS的酶复合体- 有缺陷的癌细胞。此外，我们已经证明，与目前用于 人类，我们的候选化合物可以对广泛的癌症类型有效，即使在 常氧条件。选定的药物已被证明可以保护小鼠心脏，延长寿命。 在蠕虫中，表明在活体中有良好的安全性。因此，此应用程序的主要目标是解开 在癌症中对这种新发现的ROS产生机制进行对照，以研究其治疗潜力 在小鼠身上对选定的药物进行研究，并确定对这些新方法最敏感的癌症类型。 通过成功完成拟议的研究，我们希望获得可能导致 没有多种有效和广泛适用的抗癌治疗选择。

Recent investigations on cancer metabolism have inspired a number of new ideas for anti-cancer approaches. One such promising approach is to exploit the mechanisms governing the production of reactive oxygen species (ROS) in cancer. Some oncogenic mutations as well as tumor hypoxia are known to increase ROS production in cancer cells, which may play important roles in promoting tumor growth and metastasis. However, ROS is a double-edged sword, because too much ROS can also kill cancer cells. Cancer cells inside a solid tumor often reside in a hypoxic environment, meaning that the oxygen level is much lower than it is in normal tissues. Nonetheless, most anti-cancer agents are discovered using cancer cells maintained under a normal physiological concentration of oxygen. In hypoxic conditions, cancer cells exhibit oxidative phosphorylation (OXPHOS) defects and undergo metabolic reprogramming. Consequently, they become more aggressive and resistant to commonly used therapies. Hence, therapeutic approaches that can effectively eliminate hypoxic tumors are critically needed. Using a chemical screen, we have identified a compound that induces potent cytotoxicity toward a variety of cancer cells under hypoxic conditions and cancer cells carrying OXPHOS mutations. Intriguingly, our results further suggest a surge of mitochondrial ROS as the cause of cytotoxicity and point to a previously unrecognized ROS-producing enzyme complex in OXPHOS- defective cancer cells. Moreover, we have shown that, in combination with other agents currently being used in human, our candidate compound can become effective against a broad spectrum of cancer types even in normoxic conditions. The selected agent has been shown to confer cadioprotection in mice and extend lifespan in worms, suggesting good safety profiles in vivo. Thus, the major goals of this application are to unravel the controls of this newly discovered ROS-producing machinery in cancer, to investigate the therapeutic potential of the selected agent in mice and to identify the cancer types most susceptible to these new approaches. By successfully completing the proposed research, we hope to gain critical knowledge that may lead to nultiple effective and broadly applicable anti-cancer treatment options.