Ketotherapy: Cutting carbs to treat cancer

Abstract

Dietary interventions hold promise in cancer treatments. However, clinical application has been limited by a lack of mechanistic understanding of the metabolic effects. In this issue, Yang et al. use mouse models and isotope tracing to demonstrate that the ketogenic diet induces reductive stress and primes pancreatic tumors for chemotherapy.¹.

Figure 1.

Ketogenic diet primes cancer cells for chemotherapy treatment via reductive stress. Glucose (Glc) is taken up from the environment and broken down into pyruvate (Pyr) via glycolysis. Pyr can be reversibly reduced to lactate (Lac) with the oxidation of NADH to NAD+. Pyruvate and lactate constitute a redox couple, which can help buffer the inhibitory effects of a high NADH/NAD+ ratio that occurs from increased catabolism and energy production, like that in a tumor. The ketogenic (keto) diet decreases circulating glucose, concurrent with an increase in circulating ketone bodies, like 3-hydroxybutuyrate (3HB) and acetoacetate (AcAc). Chemotherapy (Chemo) in combination with Keto limits other fuel sources (like Glc) and forces tumor cells to instead use 3HB. In tumors treated with Chemo + Keto, 3HB is unidirectionally converted into AcAc, resulting in a high NADH/NAD+ ratio, cytotoxicity, and tumor growth inhibition.