Enhancement of Cancer Therapy Using Ketogenic Diets

描述(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-羟基丁二酸酯和乙酰乙酸酯；乙酰辅酶A的前体)升高，迫使细胞更严重地依赖线粒体新陈代谢来产生能量。据推测，相对于正常细胞，癌细胞处于由O2~-和H_2O_2介导的慢性代谢性氧化应激状态，氧化剂产生的主要部位是线粒体电子传递链复合体。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严重地依赖线粒体O2代谢，那么生酮饮食将选择性地导致癌细胞氧化应激，进而有望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药物敏感。目前的提案将检验这样一种假设，即生酮饮食通过代谢氧化应激增强放化疗与葡萄糖代谢抑制剂相结合的抗癌效果。这一假设将在两个特定的目标中得到验证，第一个目标将确定2-羟基丁酸酯和/或乙酰乙酸酯是否可以通过涉及O27和H_2O_2介导的代谢氧化应激的机制，在体外增强人头颈部癌细胞(具有CIS)和胰腺癌细胞(具有吉西他滨)的2DG诱导的放化疗敏感性。第二个目的将确定生酮饮食是否能通过代谢氧化应激在体内增强2DG诱导的胰腺癌和头颈癌移植瘤模型的放射和/或化疗敏感性。如果葡萄糖和过氧化氢代谢抑制剂与生酮饮食相结合所引起的放化疗增敏可以被证实是由代谢氧化应激引起的，这项工作可能为使用相对无毒的饮食干预措施提供第一个生化基础，目的是选择性地增强癌细胞的氧化应激，并结合传统的抗癌药物，以基于癌症和正常细胞氧化代谢的根本差异来加强癌症治疗。公共卫生相关性：项目叙述：观察到癌细胞中活性氧物种水平的增加可以通过葡萄糖代谢的增加来补偿，这导致了这样的想法，即癌细胞可能在氧化代谢方面存在根本缺陷，可以利用这些缺陷来改善饮食控制的癌症治疗。目前的提案将检验这样一种假设，即生酮饮食通过代谢氧化应激增强放化疗与葡萄糖代谢抑制剂相结合的抗癌效果。如果生酮饮食联合葡萄糖代谢抑制剂引起的放化疗增敏是由代谢氧化应激引起的，这项工作可能为利用饮食干预选择性增强癌细胞的氧化应激提供新的生化基础，目的是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的癌症治疗。

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.