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Media type:
E-Article
Title:
Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy
Contributor:
Maurer, Gabriele D;
Brucker, Daniel P;
Bähr, Oliver;
Harter, Patrick N;
Hattingen, Elke;
Walenta, Stefan;
Mueller-Klieser, Wolfgang;
Steinbach, Joachim P;
Rieger, Johannes
imprint:
Springer Science and Business Media LLC, 2011
Published in:BMC Cancer
Language:
English
DOI:
10.1186/1471-2407-11-315
ISSN:
1471-2407
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized<jats:italic>in vitro</jats:italic>effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines.<jats:italic>In vivo</jats:italic>, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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.<jats:italic>In vivo</jats:italic>, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies<jats:italic>in vitro</jats:italic>, 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.</jats:p></jats:sec>