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

靶向 OXPHOS 缺陷型和 OXPHOS 功能型肿瘤中 ROS 的产生

基本信息

批准号：
10063487
负责人：
Jing-Ruey Joanna Yeh
金额：
$ 49.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063487
关键词：
Antidiabetic Drugs Antineoplastic Agents Antioxidants Bioenergetics Biological Markers Blood Cancer cell line Cell Death Cells Chemicals Citric Acid Cycle Collection Defect Electron Transport Electrons Environment Enzymes Equilibrium Exhibits FDA approved Fumarate Hydratase Glucose Glutamine Glycolysis Goals Growth Human Hypoxia In Vitro Investigation Ketoglutarate Dehydrogenase Complex Knowledge Lead Light Longevity Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Metformin Mitochondria Modification Molecular Multienzyme Complexes Mus Mutation NADH Neoplasm Metastasis Normal tissue morphology Oncogenic Oxidation-Reduction Oxidative Phosphorylation Oxygen Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Physiological Play Post-Translational Protein Processing Production Reactive Oxygen Species Regimen Renal Cell Carcinoma Reporting Research Resistance Role Safety Solid Neoplasm Sum Testing Therapeutic Tissues Toxic effect Ubiquinone Xenograft procedure alpha ketoglutarate anti-cancer anticancer treatment base cancer cell cancer type conventional therapy cost cytotoxicity effectiveness evaluation glucose metabolism in vivo inhibitor/antagonist insight mouse model neoplastic cell novel strategies novel therapeutic intervention prevent response side effect targeted treatment tumor tumor growth tumor hypoxia tumor metabolism tumor xenograft

项目摘要

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.

最近对癌症代谢的研究激发了许多抗癌的新想法接近。其中一种有希望的方法是利用控制反应产物产生的机制，氧物种（ROS）在癌症中的作用已知某些致癌突变以及肿瘤缺氧会增加癌细胞内活性氧的产生，可能在促进肿瘤生长和转移中起重要作用。然而，ROS是一把双刃剑，因为过多的ROS也可以杀死癌细胞。实体瘤内的癌细胞通常位于缺氧环境中，这意味着氧气水平比正常组织中的要低得多。尽管如此，大多数抗癌药物都是利用癌症来发现的。维持在正常生理氧浓度下的细胞。在缺氧条件下，癌细胞表现出氧化磷酸化（OXPHOS）缺陷并经历代谢重编程。因此，委员会认为，它们变得更具攻击性并且对常用的治疗具有抗性。因此，能够有效消除缺氧肿瘤的方法是非常必要的。通过化学筛选，我们发现了一种一种化合物，在缺氧条件下诱导对多种癌细胞的有效细胞毒性，携带OXPHOS突变的细胞。有趣的是，我们的研究结果进一步表明，线粒体ROS的激增，细胞毒性的原因，并指出一个以前未认识的ROS生产酶复合物OXPHOS- 缺陷癌细胞此外，我们已经表明，与目前用于治疗的其他药物结合，在人类中，我们的候选化合物可以有效地对抗广谱癌症类型，即使在常氧条件下所选的药物已被证明可以在小鼠中提供心脏保护并延长寿命在蠕虫中，表明在体内具有良好的安全性。因此，本申请的主要目标是解开控制这种新发现的癌症中产生ROS的机制，以研究治疗潜力。并确定最容易受到这些新方法影响的癌症类型。通过成功完成拟议的研究，我们希望获得关键的知识，可能导致多种有效且广泛适用的抗癌治疗选择。