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：
10322388
负责人：
Jing-Ruey Joanna Yeh
金额：
$ 48.67万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322388
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 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新思路接近。一种有希望的方法是利用控制反应性物质产生的机制。癌症中的氧（ROS）。已知一些致癌突变以及肿瘤缺氧会增加癌细胞中ROS的产生，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。实体瘤内的癌细胞通常处于缺氧环境中，这意味着氧气水平远低于正常组织中的水平。尽管如此，大多数抗癌药物都是通过癌症发现的细胞维持在正常生理氧气浓度下。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。最后，他们变得更具攻击性并且对常用疗法具有抵抗力。因此，治疗方法能否有效消除缺氧肿瘤是迫切需要的。使用化学筛选，我们已经确定了在缺氧条件下和癌症中对多种癌细胞产生有效细胞毒性的化合物携带 OXPHOS 突变的细胞。有趣的是，我们的结果进一步表明线粒体 ROS 激增细胞毒性的原因，并指向 OXPHOS- 中以前未被识别的 ROS 产生酶复合物有缺陷的癌细胞。此外，我们已经表明，与目前正在使用的其他药物相结合对于人类，我们的候选化合物可以有效对抗多种癌症类型，甚至在含氧量正常的条件。所选药物已被证明可以为小鼠提供心脏保护并延长寿命在线虫中，表明体内具有良好的安全性。因此，该应用程序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，以研究其治疗潜力在小鼠中研究所选药物，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，我们希望获得可能导致多种有效且广泛适用的抗癌治疗方案。