Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism

Bryan G Allen, Sudershan K Bhatia, Carryn M Anderson, Julie M Eichenberger-Gilmore, Zita A Sibenaller, Kranti A Mapuskar, Joshua D Schoenfeld, John M Buatti, Douglas R Spitz, Melissa A Fath, Bryan G Allen, Sudershan K Bhatia, Carryn M Anderson, Julie M Eichenberger-Gilmore, Zita A Sibenaller, Kranti A Mapuskar, Joshua D Schoenfeld, John M Buatti, Douglas R Spitz, Melissa A Fath

Abstract

Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species (ROS) such as O2(•-)and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses.

Keywords: Cancer therapy; Ketogenic diet; Oxidative stress.

© 2014 Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
Comparison of the caloric composition of the ketogenic diet, Atkins diet, and American diet. On any given day Americans consume an average of 265 g of carbohydrates (50% of total calories), 78.3 g of total fat (35% of total calories), and 78.1 g of protein (15% of total calories). Using percentage of total calories, these values are consistent with current 2010 United States Department of Agriculture recommendations that call for 45–65% of total calories from carbohydrate, 20–35% of total calories from fat, and 10–15% of total calories from protein (80).
Fig. 2
Fig. 2
Comparison of normal cell and tumor cell metabolism on an American diet and a ketogenic diet. Relative to normal cells, tumor cells have been hypothesized to have increased mitochondrial DNA mutations as well as alterations in the expression of nuclear encoded mitochondrial proteins, resulting in increased production of reactive oxygen species (ROS) during mitochondrial respiration. Increased tumor cell ROS increases tumor cell dependence upon glucose metabolism, resulting in generation of NADPH and pyruvate via the pentose phosphate shunt and pyruvate from glycolysis. NADPH and pyruvate reduce hydroperoxides. Ketogenic diets decrease the capability of tumor cells to produce NADPH because, in most tissues, fat metabolism is unable to undergo gluconeogenesis to form glucose-6-phosphate (G-6-P) necessary to enter the pentose phosphate shunt. Thus, ketogenic diets should further increase the oxidative stress in tumor cells relative to normal cells by limiting NADPH regeneration.
Fig. 3
Fig. 3
Possible acute and chronic side effects associated with the ketogenic diet.
Fig. 4
Fig. 4
(A) Ketogenic diet phase I clinical trial schema and (B) sample ketogenic diet meal with a similar 4:1 ratio of fat to carbohydrate+protein as provided in the nutritionally complete KetoCal©. Ketosis is confirmed by laboratory measurement prior to beginning radiation therapy.

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