title: Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model.
abstract: BACKGROUND
  Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer's oxidative phosphorylation system.
  
  
  METHODS
  Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content).
  
  
  RESULTS
  Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention.
  
  
  CONCLUSIONS
  Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose that a ketogenic diet and/or calorie restriction should be further evaluated as a possible adjuvant therapy for patients undergoing treatment for neuroblastoma.
authors.affiliation: Research Program for Receptor Biochemistry and Tumor Metabolism, Paracelsus Medical University, Salzburg, Austria; Division of Medical Genetics, Medical University Innsbruck, Innsbruck, Tirol, Austria.
authors.forename: Raphael Johannes
authors.initials: RJ
authors.lastname: Morscher
authors.affiliation: Research Program for Receptor Biochemistry and Tumor Metabolism, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Aminzadeh-Gohari
authors.affiliation: Research Program for Receptor Biochemistry and Tumor Metabolism, Paracelsus Medical University, Salzburg, Austria.
authors.forename: René Gunther
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Johannes Adalbert
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Department of Dermatology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Department of Pathology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Research Program for Receptor Biochemistry and Tumor Metabolism, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kofler
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics*; D031204:Caloric Restriction; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015256:Coenzyme A-Transferases / Q000378:metabolism; D004272:DNA, Mitochondrial; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D059585:G1 Phase Cell Cycle Checkpoints; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000178:diet therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D018949:Antigens, CD1; D004272:DNA, Mitochondrial; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase