Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

Abstract

BackgroundEven in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells.MethodsTo investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.ResultsThe ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.ConclusionIn summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.

The ketogenic diet for the treatment of malignant glioma

“…Unlike normal brain cells, many tumor cells cannot utilize ketones effectively due to their various genetic and mitochondrial defects, and must rely on glucose as their primary energy source ( 13,(30)(31)(32)(33)(34)(35). Ketone bodies may also be toxic to some human tumor cells (36)(37)(38).…”

Nutrition Support To Patients Undergoing Gastrointestinal Surgery

“…For several colon and breast cancer cell lines, Fine et al showed that the amount of ATP loss under treatment with acetoacetate was related to the level of UCP-2 expression. Very recently, Maurer et al demonstrated that glioma cells -although not negatively influenced by β-hydroxybutyrate -are not able to use this ketone body as a substitute for glucose when starved of the latter, contrary to benign neuronal cells [128]. This supports the hypothesis that under low glucose concentrations, ketone bodies could serve benign cells as a substitute for metabolic demands while offering no such benefit to malign cells.…”

Metabolic effects of Hedyotis diffusa on rats bearing Walker 256 tumor revealed by NMR‐based metabolomics

“…3-Hydroxybutyrate, one of important ketone bodies, is produced by liver under conditions of fasting and caloric restriction; its elevation suggests that more energy for cell proliferation is in demand, and it can compensate the shortage of energy. [35,36] Some amino acid levels presented higher in cancer than in healthy controls in some studies. [37,38] Our results were consistent with these reports that L-threonine, L-leucine, L-valine, L-glutamine, L-proline, ornithine, and citrulline were markedly increased in model rats.…”