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New Challenges to Study Heterogeneity in Cancer Redox Metabolism

机译：研究癌症氧化还原代谢异质性的新挑战

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Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine.
机译：活性氧（ROS）是重要的细胞过程中涉及的重要病理生理分子。它们在高浓度下极为有害，因为它们会促进自由基的产生以及脂质，蛋白质和核酸的氧化，从而导致细胞凋亡。 ROS的失衡和氧化还原稳态的紊乱现在被认为是复杂疾病的标志。考虑到由于线粒体功能障碍，癌细胞中的ROS水平显着增加，ROS代谢已成为开发有效治疗策略的目标，并且抗氧化剂被用作潜在的化疗药物。但是，最初针对ROS的临床试验中向患者补充了抗氧化剂的结果不一致，即改善了治疗或增加了恶性程度。这些不同的结果可能是由于不同患者的肿瘤高度异质性的氧化还原反应所致。因此，以人群为基础的治疗策略是不合适的，为有效治疗患者，需要针对患者量身定制的治疗方法。此外，由于ROS之间的串扰，降低了等效物[例如NAD（P）H]和癌症中异质的中心代谢，因此，寻找最佳治疗靶点需要考虑能够捕获复杂化合物的全系统方法在所有相关途径中观察到的改变。系统生物学和工程方法可以与个性化医学中开发的工具一起用于克服这些挑战。然而，在疾病治疗的背景下，这些方法尚未解决基于ROS和氧化还原的疗法。在这里，我们综述了ROS及其偶联的氧化还原伙伴在肿瘤发生中的作用。具体来说，我们重点介绍了在理解过氧化氢（H2O2）的作用方面的一些挑战，过氧化氢是癌症发展过程中病理生理中最重要的ROS之一。我们还讨论了其与抗氧化剂防御系统的相互作用，例如偶联的过氧化物酶/硫氧还蛋白和谷胱甘肽/谷胱甘肽过氧化物酶系统，以及其还原等效代谢。最后，我们强调需要采用系统级和针对患者的方法来阐明这些系统的作用，并通过使用个性化医学中开发的工具来确定治疗目标。

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