New Challenges to Study Heterogeneity in Cancer Redox Metabolism.
New Challenges to Study Heterogeneity in Cancer Redox Metabolism.
复制标题
DOI：
10.3389/fcell.2017.00065
复制
发表时间：
2017
影响因子：
5.5
通讯作者：
Mardinoglu A
中科院分区：
文献类型：
--
作者：
Benfeitas R;Uhlen M;Nielsen J;Mardinoglu A
活性氧（Reactive oxygen species，ROS）是参与细胞生命过程的重要病理生理分子。它们在高浓度下是极其有害的，因为它们促进自由基的产生和脂质、蛋白质和核酸的氧化，这可能导致细胞凋亡。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，ROS水平在癌细胞中显著增加，ROS代谢已成为开发有效治疗策略的目标，抗氧化剂被用作潜在的化疗药物。然而，最初的以ROS为重点的临床试验（其中向患者补充抗氧化剂）提供了不一致的结果，即，改善治疗或增加恶性肿瘤。这些不同的结果可能是由于不同患者肿瘤的高度异质性氧化还原反应。因此，基于人群的治疗策略是不合适的，需要患者定制的治疗方法来有效治疗患者。此外，由于ROS之间的串扰，还原当量[例如，由于NAD（P）H]和中心代谢在癌症中是异质性的，找到最佳治疗靶点需要考虑能够捕获在所有相关途径中观察到的复杂改变的全系统方法。系统生物学和工程方法可以用来克服这些挑战，以及在个性化医疗开发的工具。然而，基于ROS和氧化还原的疗法尚未在疾病治疗的背景下通过这些方法来解决。在这里，我们审查的作用，活性氧和他们的耦合氧化还原伙伴在肿瘤发生。具体来说，我们强调了一些挑战，在理解过氧化氢（H2 O2）的作用，其中一个最重要的活性氧在病理生理学中的癌症进展。我们还讨论了其与抗氧化防御的相互作用，如耦合peroxiredoxin/硫氧还蛋白和谷胱甘肽/谷胱甘肽过氧化物酶系统，其还原当量代谢。最后，我们强调需要系统级和患者量身定制的方法来澄清这些系统的作用，并通过使用个性化医疗开发的工具来确定治疗靶点。
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.