Is there a role for carbohydrate restriction in the treatment and prevention of cancer?

Abstract

Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake.In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.

Figure 1

PET image of a patient with a left central lung carcinoma (arrows). Note also the high FDG uptake by the kidneys (Fig D), brain and myocard (Figure E). Source: PET/CT Imaging Centre, University Hospital of Würzburg.

Figure 2

The IGF1R-IR/PI3K/Akt/mTOR pathway and its manipulation through diet. Elevations in blood glucose concentrations lead to secretion of insulin with subsequent elevation of free IGF1. Binding of insulin and IGF1 to their receptor tyrosine kinases induces autophosphorylation of the latter which leads to subsequent activation of PI3K by one of at least three different pathways [54]. Further downstream, PI3K signaling causes phosphorylation and activation of the serine/threonine kinase Akt (also known as protein kinase B). Akt activates mammalian target of rapamycin (mTOR), which itself induces aerobic glycolysis by up-regulating key glycolytic enzymes, in particular via its downstream effectors c-Myc and hypoxia inducible factor (HIF)-1α. mTOR is negatively affected through activation of AMPK, which can be achieved by dietary restriction [67]. In addition, a possible negative interaction between insulin and AMPK is discussed in vivo [60].

Figure 3

Development of the cachectic state via sustained inflammatory signaling. Glucose metabolism in peripheral tissues is impaired already at early stages, while hepatic gluconeogenesis increases during tumor progression at later stages.