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（由适用提供）：预测现代癌症疗法的发展是基于抗癌药物应通过利用特定于癌细胞的生化和物理差异来选择性地杀死癌症与正常细胞的想法。早期祖细胞“癌症干细胞”（CSC）可能代表导致治疗失败的癌细胞的亚群的观念也获得了大量的实验支持。此外，癌症和正常细胞之间氧化代谢的基本差异似乎导致活性氧的稳态水平增加（ROS； O2• - 和H2O2），并且可能代表选择性增强治疗反应的“靶标”。如果通过有选择地增强ROS的产生同时抑制水氧化剂代谢，可以将CSC的存活损害，那么可以探索CSC代谢的差异，以选择性地改善对常规放射性化学涉及的反应。初步数据表明，暴露于人类乳腺癌的早期祖细胞CSC暴露于O2的稳态水平增加了 - 相对于来自正常乳腺上皮细胞群体的干细胞。此外，ROS水平的药物操纵[具有线粒体靶向三苯基磷酸衍生物； TPP]和/或抑制谷胱甘肽（GSH）和硫氧还蛋白（TRX） - 依赖性的氢过氧代谢[使用丁二胺磺氧胺（BSO）和Auranofin（AUR）]与诱导的代谢氧气相对于正常干细胞相对依赖于CSC，以选择性地依赖于CSC。最后，TPP衍生物在动物中的耐受性良好，并且对GSH和TRX依赖性氢过氧代谢（AUR+BSO）的简单抑制可增强CSC对辐射的反应。这些初步数据导致了以下假设：旨在增加线粒体ROS产生（带有TPP衍生物）的药理操作结合了GSH-和TRX依赖性氢过氧化物代谢的抑制剂，并在CSC中引起CSSC（VS.正常干细胞）的选择性细胞毒性（Vs.正常干细胞），以及增强卵子的反应 - 以及无线电毒素 - 以及蜂房的选择性细胞毒性 - H2O2介导的氧化应激。该假设将以两个目的进行检验：1）确定用TPP衍生物的药理学操纵是否会选择性地增强氧化应激以及通过增加线粒体O2• - 和H2O2在癌症中与正常干细胞在体外和2）中的合并gsh-and trobs nifferem nyfectif gshss-gsh-niffere condects cancy-nyf gsss-dypipers nifferem----衍生物可以通过增加O2• - 和H2O2介导的氧化物胁迫来选择性地敏感的癌症与正常干细胞对化学或无线电敏感性。完成这些研究将提供详细的机械理解，以了解使用线粒体ROS的操作与水过氧化物代谢抑制剂结合使用以选择性地杀死癌症干细胞的潜力。这项工作解决了利用改变干细胞氧化物代谢以增强癌症治疗所必需的癌症生物学问题。