Cancer Therapy: Preclinical Ketogenic Diets Enhance Oxidative Stress and Radio- Chemo-Therapy Responses in Lung Cancer Xenografts

Purpose: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radiochemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. ExperimentalDesign:MicebearingNCI-H292andA549 lung cancer xenograftswere fed aketogenic diet (KetoCal 4:1 fats: proteinsþcarbohydrates) and treated with either conventionally fractionated (1.8–2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)–modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and gH2AX as indices of proliferation and DNA damage, respectively. Results:The ketogenic diets combinedwith radiation resulted in slower tumor growth inbothNCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. Conclusions: These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by amechanism that may involve increased oxidative stress. Clin Cancer Res; 19(14);