Enhancement of Cancer Therapy Using Ketogenic Diets

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-羟基丁酸酯和乙酰乙酸酯；乙酰辅酶a的前体）升高，迫使细胞更多地依赖线粒体代谢来产生能量。据推测，相对于正常细胞，癌细胞处于由O2"-和H2O2介导的慢性代谢氧化应激状态，促氧化剂的主要产生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）线粒体氧代谢有缺陷，导致慢性代谢氧化应激，而生酮饮食迫使癌细胞更多地依赖线粒体氧代谢，那么生酮饮食将有选择性地导致癌细胞氧化应激，进而有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。目前的提议将验证生酮饮食通过代谢氧化应激增强放射化疗联合葡萄糖代谢抑制剂的抗癌作用的假设。这一假设将在两个特定目标中进行验证，第一个目标是确定是否可以通过O27-和H2O2介导的代谢氧化应激机制，在体外用2-羟基丁酸酯和/或乙酰乙酸酯增强人头颈癌细胞（使用CIS）和胰腺癌细胞（使用吉西他滨）中2dg诱导的放化疗致敏。第二个目的是确定生酮饮食是否可以通过代谢氧化应激增强2dg诱导的胰腺癌和头颈部肿瘤异种移植模型体内的放射和/或化学致敏。如果葡萄糖和氢过氧化物代谢抑制剂与生酮饮食联合引起的化学放射致敏可以被证实是由代谢氧化应激引起的，这项工作为利用相对无毒的饮食干预，选择性地增强癌细胞的氧化应激，结合常规抗癌药物，基于癌症与正常细胞氧化代谢的根本差异，加强癌症治疗提供了第一个生化基础。公共卫生相关性：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，这导致了这样一种观点，即癌细胞可能在氧化代谢方面存在根本缺陷，可以利用饮食操纵来改善癌症治疗。目前的提议将验证生酮饮食通过代谢氧化应激增强放射化疗联合葡萄糖代谢抑制剂的抗癌作用的假设。如果生酮饮食联合糖代谢抑制剂引起的化疗-放射致敏可以被证实是由代谢氧化应激引起的，这项工作可以为利用饮食干预选择性地增强癌细胞中的氧化应激提供新的生化基础，从而基于癌症与正常细胞氧化代谢的根本差异改进传统的癌症治疗方法。

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.