Enhancement of Cancer Therapy Using Ketogenic Diets

使用生酮饮食增强癌症治疗

• 批准号: 7639109
• 负责人: Douglas Robert Spitz
• 金额: $ 19.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7639109
• 关键词: Acetoacetates; Acetyl Coenzyme A; Antineoplastic Agents; Biochemical; Blood; Blood Glucose; Carbohydrates; Cell Respiration; Cells; Chronic; Cisplatin; Complex; Data; Defect; Deoxyglucose; Dietary Intervention; Dose; Drug Metabolic Detoxication; Electron Transport; Energy Metabolism; Epilepsy; Fatty acid glycerol esters; Glucose; Glycolysis; Head and Neck Cancer; Head and neck structure; Human; Hydrogen Peroxide; In Vitro; Ketones; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Normal Cell; Oxidative Stress; Pancreas; Play; Pre-Clinical Model; Production; Proteins; Radiation therapy; Radio; Reactive Oxygen Species; Relative (related person); Reporting; Research; Respiration; Role; Signal Transduction Pathway; Site; Testing; Therapeutic; Therapeutic Agents; Work; Xenograft Model; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytotoxicity; deprivation; gemcitabine; glucose metabolism; improved; in vivo; inhibitor/antagonist; ketogenic diet; nervous system disorder; novel; public health relevance; success; tumor xenograft

DESCRIPTION (provided by applicant): Ketogenic diets, which are low in protein and carbohydrates and high in fats, result in elevated ketones (2-hydroxybuturate and acetoacetate; precursors to Acetyl-CoA) forcing cells to rely more heavily on mitochondrial metabolism for energy production. It has been hypothesized that cancer cells, relative to normal cells, exist in a condition of chronic metabolic oxidative stress mediated by O2"- and H2O2, with a major site of pro-oxidant production being mitochondrial electron transport chain complexes. If cancer cells (relative to normal cells) have defective mitochondrial O2 metabolism that results in chronic metabolic oxidative stress and ketogenic diets force cancer cells to rely more heavily on mitochondrial O2 metabolism, then ketogenic diets would be expected to selectively cause oxidative stress in cancer cells which in turn would be expected to selectively sensitize cancer cells to conventional cancer therapeutic agents that cause cell killing via oxidative stress. The current proposal will test the hypothesis that ketogenic diets enhance the anti-cancer effects of radio-chemo-therapy combined with inhibitors of glucose metabolism via metabolic oxidative stress. This hypothesis will be tested in two specific aims the first of which will determine if 2DG-induced radio-chemo-sensitization can be enhanced in vitro with 2- hydroxybuturate and/or acetoacetate in human head and neck cancer cells (with CIS) and pancreatic cancer cells (with gemcitabine) via a mechanism involving O27- and H2O2 mediated metabolic oxidative stress. The second aim will determine if ketogenic diets can enhance 2DG-induced radio and/or chemo- sensitization in vivo in human tumor xenograft models of pancreatic and head and neck cancer via metabolic oxidative stress. If chemo-radio-sensitization caused by inhibitors of glucose and hydroperoxide metabolism combined with ketogenic diets can be confirmed to be caused by metabolic oxidative stress, this work could provide the first biochemical rationale for using relatively non-toxic dietary interventions aimed at selectively enhancing oxidative stress in cancer cells combined with conventional anti-cancer agents for the purpose of enhancing cancer therapy based on fundamental differences between cancer and normal cell oxidative metabolism. PUBLIC HEALTH RELEVANCE: Project Narrative: The observation that Increase levels of reactive oxygen species in cancer cells may compensated for by increases in glucose metabolism has led to the idea that cancer cells may have fundamental defects in oxidative metabolism that can be exploited to improve cancer therapy with dietary manipulations. The current proposal will test the hypothesis that ketogenic diets enhance the anti-cancer effects of radio-chemo-therapy combined with inhibitors of glucose metabolism via metabolic oxidative stress. If chemo-radio-sensitization caused by ketogenic diets combined with inhibitors of glucose metabolism can be confirmed to be caused by metabolic oxidative stress, this work could provide a novel biochemical rationale for using dietary interventions to selectively enhance oxidative stress in cancer cells for the purpose of improving conventional cancer therapies based on fundamental differences between cancer and normal cell oxidative metabolism.

描述（由申请人提供）：生酮饮食，蛋白质和碳水化合物低，脂肪含量高，导致酮（2-羟基丁酸酯和乙酰乙酸乙酸酯言和乙酰乙酸的前体；乙酰基-COA的前体）迫使细胞迫使细胞更严重地依赖于线粒体的能量生产。 It has been hypothesized that cancer cells, relative to normal cells, exist in a condition of chronic metabolic oxidative stress mediated by O2"- and H2O2, with a major site of pro-oxidant production being mitochondrial electron transport chain complexes. If cancer cells (relative to normal cells) have defective mitochondrial O2 metabolism that results in chronic metabolic oxidative stress and ketogenic diets force cancer cells to rely more在线粒体O2代谢上的严重性，则有望在癌细胞中选择性地导致氧化应激，而癌细胞将有望将癌细胞选择性地敏感到癌细胞对常规的癌细胞治疗剂，从而导致细胞通过氧化应激促进氧化饮食的抗饮食效果，从而可以增强抗蛋白饮食。通过代谢氧化应激的葡萄糖代谢将在两个特定的目标中进行测试。首先，将确定2DG诱导的放射性化学敏感性是否可以通过2-羟基丁酸酯和/或乙酸乙酸酯和甲壳酸细胞（与CIS和颈部癌细胞）（与CanciT癌症）（panciT cancerical cancer canceric cancel canceric cancer）一起在体外增强。 H2O2介导的代谢氧化应激。第二个目标将确定生酮饮食是否可以通过代谢氧化应激在人类肿瘤异种移植模型中增强2DG诱导的胰腺和头颈癌的体内2DG诱导的无线电和/或化学敏化。如果通过葡萄糖和氢过氧代谢抑制剂与生酮饮食相结合的化学性腺敏化作用可以证实是由代谢氧化应激引起的，那么这项工作可以提供第一种生物化学理由，用于使用相对非毒性的饮食抗体，在癌细胞中促进癌细胞的相对良好的氧化量，以选择癌细胞的癌细胞组合量，以癌细胞的方式促进癌细胞的组合性，使癌细胞合并癌细胞的组合量。关于癌症与正常细胞氧化代谢之间的基本差异。公共卫生相关性：项目叙述：癌细胞中增加活性氧的水平可能会通过葡萄糖代谢增加而弥补的观察结果，这使得癌细胞可能在氧化代谢中具有根本缺陷，这些缺陷可以被利用以改善饮食中的癌症治疗。当前的提案将检验以下假设：生酮饮食可以通过代谢氧化应激增强了无线电治疗的抗癌作用以及葡萄糖代谢的抑制剂。如果可以证实是由生酮饮食与葡萄糖代谢抑制剂相结合的化学哈迪奥敏化，这可以证实是由代谢氧化应激引起的，那么这项工作可以为基于常规癌症的常规癌症和常规率提供癌细胞的选择性增强氧化应激的饮食干预措施提供新颖的生化干预措施，以增强氧化应激细胞。