Enhancing Metabolic Oxidative Stress and Therapy Responses in Cancer Stem Cells

增强癌症干细胞的代谢氧化应激和治疗反应

• 批准号: 8776281
• 负责人: Douglas Robert Spitz
• 金额: $ 33.84万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776281
• 关键词: Address; Animals; Antineoplastic Agents; Auranofin; Biochemical; Breast Carcinoma; Breast Epithelial Cells; Buthionine Sulfoximine; Cancer Biology; Cell Respiration; Cell Survival; Chronic; Clinical Trials; Data; Development; Electron Transport; Electrons; Exhibits; Figs - dietary; Genomic Instability; Glucose; Glutathione; Growth; Health; Human; Hydrogen Peroxide; In Vitro; Lead; Malignant Neoplasms; Mediating; Metabolic; Metabolic stress; Metabolism; Mitochondria; Normal Cell; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Physiological; Population; Production; Radiation Tolerance; Reaction; Reactive Oxygen Species; Regulation; Relative (related person); Resistance; Signal Transduction; Stem cells; Superoxides; Testing; Therapeutic; Thioredoxin; Translating; Treatment Failure; Undifferentiated; Warburg Effect; Work; base; cancer cell; cancer stem cell; cancer therapy; chemoradiation; cytotoxicity; design; glucose metabolism; improved; in vivo; inhibitor/antagonist; killings; progenitor; radiation response; response; therapy resistant; tumor

DESCRIPTION (provided by applicant): The development of modern cancer therapies is predicated on the idea that anticancer agents should selectively kill cancer vs. normal cells by exploiting biochemical and physiological differences specific to cancer cells. The notion that early progenitor "cancer stem cells" (CSCs) may represent a subpopulation of cancer cells contributing to treatment failure has also gained significant experimental support. Furthermore, fundamental differences in oxidative metabolism between cancer and normal cells appear to lead to increased steady-state levels of reactive oxygen species (ROS; O2•- and H2O2) and may represent a "target" for selectively enhancing therapeutic responses. If survival of CSCs could be compromised by selectively enhancing the production of ROS while inhibiting hydroperoxide metabolism, then differences in CSC metabolism could be exploited to selectively improve responses to conventional radio-chemo-therapies. Preliminary data shows that early progenitor CSCs from human breast carcinoma population exhibit increased steady-state levels of O2•-- relative to stem cells derived from normal breast epithelial cell populations. In addition, pharmacological manipulations of ROS levels [with mitochondrial targeted triphenylphosphonium derivatives; TPP] and/or inhibition of glutathione (GSH)- and thioredoxin (Trx)- dependent hydroperoxide metabolism [using buthionine sulfoximine (BSO) and Auranofin (AUR)] is shown to selectively deplete CSCs, relative to normal stem cells by inducing metabolic oxidative stress. Finally, TPP derivatives are well tolerated in animals and simultaneous inhibition of GSH- and Trx-dependent hydroperoxide metabolism (AUR+BSO) enhances CSCs responses to radiation. These preliminary data led to the hypothesis that pharmacological manipulations designed to increase mitochondrial ROS production (with TPP derivatives) combined with inhibitors of GSH- and Trx- dependent hydroperoxide metabolism will cause selective cytotoxicity in CSCs (vs. normal stem cells) as well as enhance tumor responses to radio-chemo-therapies by increasing O2•-- and H2O2-mediated oxidative stress. This hypothesis will be tested in two Aims to: 1) Determine if pharmacological manipulations with TPP derivatives will selectively enhance oxidative stress as well as chemo-radio-sensitivity by increasing mitochondrial O2•-- and H2O2 in cancer vs. normal stem cells in vitro and in vivo and 2) Determine if simultaneous inhibition of GSH- and Trx-dependent hydroperoxide metabolism combined with TPP derivatives can selectively sensitize cancer vs. normal stem cells to chemo- or radio-sensitivity by increasing O2•- and H2O2-mediated oxidative stress. Completing these studies will provide a detailed mechanistic understanding of the potential for using manipulations of mitochondrial ROS in combination with inhibitors of hydroperoxide metabolism to selectively kill cancer stem cells. This work addresses a critical question in cancer biology necessary for exploiting altered stem cell oxidative metabolism to enhance cancer therapy.

描述（由申请人提供）：现代癌症疗法的发展基于这样的想法：抗癌剂应该通过利用癌细胞特有的生化和生理差异来选择性地杀死癌症与正常细胞，即早期祖细胞“癌症干细胞”的概念。 （CSC）可能代表导致治疗失败的癌细胞亚群，这也获得了重要的实验支持。此外，癌症和正常细胞之间氧化代谢的根本差异似乎导致活性氧的稳态水平增加。如果可以通过选择性增强 ROS 的产生同时抑制氢过氧化物代谢来损害 CSC 的存活，那么可以利用 CSC 代谢的差异。选择性地改善对传统放化疗的反应 初步数据表明，相对于正常干细胞，来自人类乳腺癌群体的早期祖细胞表现出更高的稳态 O2水平。此外，对 ROS 水平进行药理学操作（使用线粒体靶向三苯基鏻衍生物）和/或抑制谷胱甘肽 (GSH) 和硫氧还蛋白 (Trx) 依赖性氢过氧化物代谢 [使用丁硫氨酸亚磺酰亚胺 (BSO) 和金诺芬 (Auranofin)。 (AUR)] 通过诱导代谢氧化应激，相对于正常干细胞，可选择性地消耗 CSC。最后，TPP 衍生物在动物中具有良好的耐受性，同时抑制 GSH 和 Trx 依赖性氢过氧化物代谢 (AUR+BSO) 可增强 CSC 对辐射的反应。这些初步数据得出了这样的假设：旨在增加线粒体 ROS 产生的药理学操作（与TPP 衍生物）与 GSH 和 Trx 依赖性氢过氧化物代谢抑制剂相结合，将在 CSC（相对于正常干细胞）中引起选择性细胞毒性，并增强肿瘤对通过增加 O2•-- 和 H2O2 介导的氧化应激来进行放射化疗 该假设将在两个方面进行检验 目的是： 1) 确定 TPP 衍生物的药理操作是否会选择性地增强氧化应激以及化学放射敏感性。通过在体外和体内增加癌症与正常干细胞中的线粒体 O2•-- 和 H2O2 以及 2) 确定是否同时抑制 GSH- 和Trx 依赖性氢过氧化物代谢与 TPP 衍生物相结合，可以通过增加 O2•- 和 H2O2 介导的氧化应激，选择性地使癌症相对于正常干细胞对化学或放射敏感性敏感。完成这些研究将为人们提供对潜在的详细机制的了解。这项工作解决了癌症生物学中利用干细胞所必需的一个关键问题。氧化代谢增强癌症治疗。