Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation

Abstract

Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R’s of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K–Akt–mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K–Akt–mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.

Foods as a Novel Treatment for Glioblastoma

“…[37] In addition, Insulin-like Growth Factor-1 (IGF-1) and glucose have been reduced in tumor cells in response to genotoxic stress. [38] The other studies described that KD and CR can boost the immune system. Moreover, the suppressed immune system in mouse models of malignant glioma could be reversed by KD and CR.…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…1). Evidence that each of these factors can be modified through ketogenic therapy has been reviewed by us recently [42,44]. …”

“…Consistently, experiments depriving cancer cells of glucose have associated cell death with both energy stress [34,35] and oxidative stress [36,37,38,39,40]. Targeting this weakness of tumor cell metabolism through nutritional strategies has recently gained interest as a measure to support pro-oxidative therapies such as ionizing radiation (IR) or hyperbaric oxygen (HBO) [41,42,43,44]. The majority of newly diagnosed cancer patients will be confronted with radiotherapy (RT) at some point during their treatment [45].…”

“…Therefore, any intervention that selectively inhibits the defense mechanisms of tumor cells and/or increases the resistance of normal cells to IR would be a highly valuable addition to this standard treatment. In this article, I summarize the evidence for using ketogenic therapy to improve the therapeutic window in RT, with the incorporation of newer findings that have been published since our first review on this topic [42]. …”

Clinical Observation of a Novel, Complementary, Immunotherapeutic Approach based on Ketogenic Diet, Chondroitin Sulfate, Vitamin D₃, Oleic Acid and a Fermented Milk and Colostrum Product

“…Thus, they reduce the synthesis de novo of a second messenger deriving from glycolysis, diacylglycerol, that is responsible for increased resistance to the killing effects of ionizing radiations (Chiarugi et al, 1989;Ruggiero et al, 1992). It can be hypothesized that decreased synthesis of diacylglycerol may be responsible for the increased sensitivity to the therapeutic effects of radiation therapy that has been observed with the implementation of ketogenic diets (Klement and Champ, 2014). In addition, it has been recently demonstrated that ketone bodies have antiinflammatory, pro-immunogenic properties that are quite relevant in the context of an integrated immunotherapeutic approach to cancer and other diseases associated with chronic inflammation and immunodeficiency (Youm et al, 2015).…”