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.

Fig. 1

Nutrient deprivation via alternate day fasting (a) or overall caloric restriction (b) synergistically work with radiation therapy to significantly slow tumor growth and downregulate several key pathways (c). AL ad libitum feeding, CR calorie restriction (taken with permission from Saleh et al. [21])

Fig. 2

Calorie restriction (CR) and a ketogenic diet (KD) target the same molecular pathways that are also targeted individually by drugs to improve cancer treatment outcomes. Arrows indicate activation, truncated lines inhibition. Carbohydrate (CHO) restriction up-regulates fatty acid oxidation and ketogenesis (beneficial for normal tissues) and impairs glycolysis and glutaminolysis (detrimental to tumor cells). See Section 2 for more details

Fig. 3

Illustration of a typical tumor control probability (solid blue line) and normal tissue complication probability (red solid line) curve as a function of total dose delivered to the tumor. We argue that CR and possibly a KD may increase the therapeutic window by favorably affecting both curves, i.e. a differential response between tumor and normal tissue

Fig. 4

The five R’s of radiobiology

Fig. 5

Proposed workflow of implementing dietary manipulation for cancer patients based on the results from an initial assessment