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，会导致酮（2-羟基丁酸和乙酰乙酸；乙酰辅酶A的前体）升高，迫使细胞更加依赖线粒体代谢获取能量生产。据推测，相对于正常细胞，癌细胞处于由 O2- 和 H2O2 介导的慢性代谢氧化应激状态，其中促氧化剂产生的主要部位是线粒体电子传递链复合物。如果癌细胞（相对于正常细胞）线粒体O2代谢有缺陷，导致慢性代谢氧化应激，生酮饮食迫使癌细胞更加依赖线粒体O2代谢，那么生酮饮食有望选择性地引起癌细胞的氧化应激反过来，预计这将选择性地使癌细胞对通过氧化应激导致细胞死亡的传统癌症治疗剂敏感。目前的提议将检验生酮饮食增强放化疗与抑制剂相结合的抗癌作用的假设。该假设将在两个具体目标中进行测试，第一个目标将确定 2-羟基丁酸和/或乙酰乙酸是否可以在体外增强 2DG 诱导的放射化学增敏作用。通过涉及 O27- 和 H2O2 介导的代谢氧化应激的机制，人类头颈癌细胞（使用 CIS）和胰腺癌细胞（使用吉西他滨）。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胰腺癌和头颈癌的人类肿瘤异种移植模型中增强 2DG 诱导的体内放射和/或化疗敏感性。如果葡萄糖和氢过氧化物代谢抑制剂与生酮饮食相结合引起的化学放射敏感性可以被证实是由代谢性氧化应激引起的，那么这项工作可以为使用旨在选择性增强氧化应激的相对无毒的饮食干预措施提供第一个生化原理。基于癌症和正常细胞氧化代谢之间的根本差异，将癌细胞中的应激与常规抗癌药物相结合，以增强癌症治疗。公共健康相关性：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，这导致人们认为癌细胞可能存在氧化代谢的基本缺陷，可以利用这些缺陷来改善癌症治疗通过饮食控制。目前的提案将检验生酮饮食通过代谢氧化应激增强放化疗联合葡萄糖代谢抑制剂的抗癌作用的假设。如果生酮饮食联合葡萄糖代谢抑制剂引起的放化疗增敏可以被证实是由代谢性氧化应激引起的，那么这项工作可以为利用饮食干预选择性增强癌细胞氧化应激的目的提供新的生化原理。基于癌症和正常细胞氧化代谢之间的根本差异来改进传统癌症疗法。