The Warburg effect and tumor hypoxia underlie a unique cancer metabolism characterized by glucose dependency and abnormal mitochondrial function. We have previously shown that this phenotype can be exploited therapeutically by glucose restriction with the ketogenic diet, dietary ketone supplementation, or hyperbaric oxygen (HBOT). We hypothesized that combining these therapies would be an
... [Show full abstract] effective non‐toxic treatment regimen, so we tested this combination therapy in the VM‐M3 mouse model of metastatic cancer. Treated mice exhibited decreased tumor growth rate, tumor vascularization, and metastatic spread, and lived twice as long as controls. To further characterize the effects of these therapies, we measured proliferation, viability, ROS production, and expression of key signaling molecules in VM‐M3 cells exposed to the following conditions: high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT). Proliferation and viability of VM‐M3 cells were significantly decreased in LG, βHB, HBOT, and combination‐treated cells at all‐time points tested. ROS (superoxide) production was increased in HBOT and combination‐treated cells compared to controls. Treatment with βHB significantly decreased expression of HIF‐1α and pAkt in VM‐M3 cells while HBOT inhibited HIF‐1α expression but increased pAkt expression. This data strongly supports further investigation into mechanisms of action and the use of these metabolic therapies as a potential cancer treatment.