Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth

13C-2H isotope tracing studies reveal that the 3HB is unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose’s concentration and TCA cycle contribution, enhances 3HB’s concentration and TCA contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system.

13C-2H同位素示踪研究表明，3-羟基丁酸（3HB）单向氧化生成NADH。此现象与由碳水化合物衍生的羧酸乳酸和丙酮酸迅速相互转换，缓冲NADH/NAD之间的平衡形成鲜明对比。在鼠类胰腺肿瘤中，生酮饮食降低了葡萄糖的浓度和三羧酸循环的贡献，提高了3HB的浓度和三羧酸循环的贡献，并适度提高NADH的水平，但对肿瘤生长无显著影响。相反，生酮饮食与细胞毒化疗的结合显著提高了肿瘤中的NADH水平，并协同抑制肿瘤生长，使化疗单独使用时的生存益处增加三倍。在免疫缺陷小鼠中，化疗与生酮饮食亦表现出协同作用，尽管仅在免疫系统完整的小鼠中观察到长期生长抑制。