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含量低，脂肪含量高，导致酮（2-羟基丁酸和乙酰乙酸;乙酰辅酶A的前体）升高，迫使细胞更严重地依赖线粒体代谢产生能量。据推测，相对于正常细胞，癌细胞存在于由O2-和H2 O2介导的慢性代谢氧化应激的条件下，其中促氧化剂产生的主要位点是线粒体电子传递链复合物。如果癌细胞（相对于正常细胞）具有缺陷的线粒体O2代谢，这导致慢性代谢氧化应激和生酮饮食迫使癌细胞更严重地依赖于线粒体O2代谢，那么生酮饮食将预期选择性地在癌细胞中引起氧化应激，氧化应激目前的提议将检验生酮饮食通过代谢氧化应激增强放化疗法与葡萄糖代谢抑制剂组合的抗癌作用的假设。将在两个特定目标中检验该假设，第一个目标将确定在体外是否可以通过涉及O27-和H2 O2介导的代谢氧化应激的机制，在人头颈癌细胞（CIS）和胰腺癌细胞（吉西他滨）中使用2-羟基丁酸和/或乙酰乙酸增强2DG诱导的放射-化学增敏作用。第二个目的是确定生酮饮食是否可以通过代谢氧化应激在胰腺癌和头颈癌的人肿瘤异种移植模型中增强体内2DG诱导的放射和/或化学敏化。如果葡萄糖和氢过氧化物代谢抑制剂结合生酮饮食引起的化学放射增敏可以证实是由代谢性氧化应激引起的，这项工作可以为使用相对无毒的饮食干预提供第一个生物化学原理，目的是选择性地增强癌细胞中的氧化应激，基于癌症和正常细胞氧化代谢之间的根本差异，用于增强癌症治疗的癌症药剂。公共卫生关系：项目叙述：观察到癌细胞中活性氧水平的增加可以通过葡萄糖代谢的增加来补偿，这导致了癌细胞可能在氧化代谢中具有根本缺陷的想法，可以利用这些缺陷来改善通过饮食操作的癌症治疗。目前的提议将检验生酮饮食通过代谢氧化应激增强放化疗法与葡萄糖代谢抑制剂组合的抗癌作用的假设。如果生酮饮食结合葡萄糖代谢抑制剂引起的化学放射增敏可以证实是由代谢氧化应激引起的，这项工作可以提供一种新的生物化学原理，用于使用饮食干预选择性地增强癌细胞中的氧化应激，以改善基于癌症和正常细胞氧化代谢之间的根本差异的传统癌症治疗。