Open Access Highly Accessed Research article

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

Gabriele D Maurer1, Daniel P Brucker1, Oliver Bähr1, Patrick N Harter2, Elke Hattingen3, Stefan Walenta4, Wolfgang Mueller-Klieser4, Joachim P Steinbach1 and Johannes Rieger1*

Author Affiliations

1 Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Schleusenweg 2-16, 60528 Frankfurt, Germany

2 Institute of Neurology (Edinger Institute), Goethe University Hospital, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt, Germany

3 Institute of Neuroradiology, Goethe University Hospital, Schleusenweg 2-16, 60528 Frankfurt, Germany

4 Institute of Physiology and Pathophysiology, Gutenberg University Medical Center, Duesbergweg 6, 55099 Mainz, Germany

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BMC Cancer 2011, 11:315  doi:10.1186/1471-2407-11-315

Published: 26 July 2011

Abstract

Background

Even 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.

Methods

To 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.

Results

The 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.

Conclusion

In 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.