The influence of ketogenic therapy on the 5 R's of radiobiology

Purpose: Radiotherapy (RT) is a mainstay in the treatment of solid tumors and works by inducing free radical stress in tumor cells, leading to loss of reproductive integrity. The optimal treatment strategy has to consider damage to both tumor and normal cells and is determined by five factors known as the 5 R's of radiobiology: Reoxygenation, DNA repair, radiosensitivity, redistribution in the cell cycle and repopulation. The aim of this review is (i) to present evidence that these 5 R's are strongly influenced by cellular and whole-body metabolism that in turn can be modified through ketogenic therapy in form of ketogenic diets and short-term fasting and (ii) to stimulate new research into this field including some research questions deserving further study. Conclusions: Preclinical and some preliminary clinical data support the hypothesis that ketogenic therapy could be utilized as a complementary treatment in order to improve the outcome after RT, both in terms of higher tumor control and in terms of lower normal tissue complication probability. The first effect relates to the metabolic shift from glycolysis toward mitochondrial metabolism that selectively increases ROS production and impairs ATP production in tumor cells. The second effect is based on the differential stress resistance phenomenon, which is achieved when glucose and growth factors are reduced and ketone bodies are elevated, reprogramming normal but not tumor cells from proliferation toward maintenance and stress resistance. Underlying both effects are metabolic differences between normal and tumor cells that ketogenic therapy seeks to exploit. Specifically, the recently discovered role of the ketone body beta-hydroxybutyrate as an endogenous class-I histone deacetylase inhibitor suggests a dual role as a radioprotector of normal cells and a radiosensitzer of tumor cells that opens up exciting possibilities to employ ketogenic therapy as a cost-effective adjunct to radiotherapy against cancer.