Abstract
The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.
Highlights
Cancers exhibit a dysregulated metabolic phenotype characterized by lactate fermentation in the presence of oxygen, a phenomenon known as the Warburg effect [1]
Tumor bioluminescence was decreased in the triple-treatment mice compared to control at weeks 1 and 2, suggesting that the physiological environment induced by our metabolic therapy was less conducive to tumor growth and may have slowed growth of the primary tumor as well as metastatic spread
Morphological and immunohistochemical analysis of livers from ketogenic diet (KD)+Ketone Ester (KE)+Hyperbaric oxygen therapy (HBOT) treated mice revealed only micrometastatic lesions with little notable vascularization compared to controls (Fig 4)
Summary
The major goal of this study was to investigate the anticancer efficacy of a novel combination of metabolic therapies—the ketogenic diet, ketone supplementation, and hyperbaric oxygen—in a mouse model of aggressive metastatic cancer that recapitulates much of the metastatic phenotype seen in invasive human cancers [53, 57–59]
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