title: Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Schleusenweg 2-16, 60528 Frankfurt, Germany.
authors.forename: Gabriele D
authors.initials: GD
authors.lastname: Maurer
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Brucker
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.forename: Stefan
authors.initials: S
authors.lastname: Walenta
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Johannes
authors.initials: J
authors.lastname: Rieger
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism / Q000494:pharmacology; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015256:Coenzyme A-Transferases / Q000235:genetics / Q000378:metabolism; D055423:Diet, Ketogenic; D005260:Female; D005910:Glioma / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006884:Hydroxybutyrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007657:Ketone Bodies / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D007657:Ketone Bodies; D006884:Hydroxybutyrate Dehydrogenase; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase; D005947:Glucose; D020155:3-Hydroxybutyric Acid