Dietary carbohydrate restriction inhibits progression of murine hepatocellular carcinoma

Introduction Metabolic reprogramming is a hallmark of cancer and the growth and survival of neoplastic cells depends on nutrients such as glucose, glutamine and certain amino acids. The effect of dietary interventions on cancer growth is currently under intense investigation. Dietary carbohydrate restriction (DCR) has shown tumor inhibition in various rodent tumor models. Mechanistically, reduced glucose supply to neoplastic cells is considered to be of functional relevance for the anti-tumor effect of dietary CR. Aim: We sought to analyze the impact of DCR on tumor progression of a murine hepatocellular carcinoma (HCC) model with special emphasis on the tumor microenvironment (TME). Methods: We took advantage of a transgenic (SV40 T antigen-driven) murine HCC model with a marked Warburg effect and observed significant tumor inhibition upon feeding of two different DCR approaches, a “low carb high protein” (LCHP) and a “low carb high fat” (LCHF, ketogenic diet) chow. Interestingly, subsequent analyses displayed marked differences between the diet groups. While the ketogenic diet resulted in significant alterations of adaptive immune cells in the TME, no such effect was detectable in mice fed the LCHP chow. LCHP, on the other hand, led to significantly enhanced oxidative stress in HCC cells, a phenomenon not observed upon LCHF feeding. In line, the anti-oxidant NAC (N-acetyl cysteine) reversed only the tumor-inhibiting effect of LCHP and not of LCHF. Conclusions: These results suggest that the intake of fat and protein is an important determinant of the tumor-inhibiting effects of low carbohydrate diets. As DCR has been safely used for almost a century, clinical application of these results seems feasible.

Publication History

Article published online:
19 August 2022