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: 8623548
• 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/8623548
• 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; Radiation Tolerance; Radio; 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; cytotoxicity; design; glucose metabolism; improved; in vivo; inhibitor/antagonist; killings; progenitor; 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(申请人提供)：现代癌症疗法的发展是基于这样的想法，即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和正常细胞。早期祖细胞“癌症干细胞”(CSCs)可能代表了导致治疗失败的癌细胞亚群，这一观点也得到了重要的实验支持。此外，癌症细胞和正常细胞之间氧化代谢的根本差异似乎导致了活性氧物种(ROS；O2和H2O2)的稳态水平增加，并可能代表着选择性增强治疗反应的“靶点”。如果在抑制氢过氧化氢代谢的同时，选择性地增强ROS的产生，可以降低CSCs的存活率，那么CSC代谢的差异可以被用来选择性地改善对传统放化疗的反应。初步数据显示，与来自正常乳腺上皮细胞群体的干细胞相比，来自人类乳腺癌群体的早期前体CSCs显示出稳定的O2？-水平升高。此外，药物操纵ROS水平[与线粒体靶向的三苯基膦衍生物；TPP]和/或抑制依赖谷胱甘肽(GSH)和硫氧还蛋白(TRX)的氢过氧化氢代谢[使用丁硫氨酸亚磺胺(BSO)和金诺芬(AUR)]被证明通过诱导代谢氧化应激来选择性地消耗CSCs。最后，TPP衍生物在动物中具有良好的耐受性，同时抑制依赖GSH和TRX的氢过氧化氢代谢(AUR+BSO)可增强CSCs对辐射的反应。这些初步数据导致了一种假设，即旨在增加线粒体ROS产生(使用TPP衍生物)的药物操作与依赖GSH和Trx的氢过氧化氢代谢抑制剂相结合，将在CSCs(与正常干细胞相比)中引起选择性细胞毒性，并通过增加O2？和H2O2介导的氧化应激来增强肿瘤对放化疗的反应。这一假说将在两个目标进行验证：1)确定TPP衍生物的药理操作是否会通过增加肿瘤与正常干细胞在体外和体内的线粒体O2？-和H2O2来选择性地增强氧化应激和放化疗敏感性；2)确定同时抑制依赖GSH和TRX的氢过氧化氢代谢与TPP衍生物联合使用是否可以通过增加O2？-和H2O2介导的氧化应激而选择性地使癌症与正常干细胞对化疗或放射敏感性增敏。完成这些研究将为利用线粒体ROS的操纵和氢过氧化氢代谢抑制剂选择性地杀死癌症干细胞的潜力提供详细的机制理解。这项工作解决了癌症生物学中的一个关键问题，利用改变的干细胞氧化代谢来加强癌症治疗是必要的。