title: Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.
abstract: What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth.
  
  
  OBJECTIVE
  To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer.
  
  
  METHODS
  120 nude athymic male mice (aged 6-8 weeks) were injected s.c. in the flank with 1.0 × 10(5) LAPC-4 prostate cancer cells. • Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition. • Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. • Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal-Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis. • All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal-Wallis and linear regression analysis, respectively.
  
  
  RESULTS
  There were no significant differences in tumour volumes among the four groups (P= 0.09). • When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P < 0.001).
  
  
  CONCLUSIONS
  Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. • MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.
authors.affiliation: Division of Urologic Surgery, Department of Surgery and the Duke Prostate Center, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kim
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Masko
authors.forename: Susan L
authors.initials: SL
authors.lastname: Poulton
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Kennedy
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
mesh_terms: D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D050528:Diet, Carbohydrate-Restricted; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D002149:Energy Intake; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D009363:Neoplasm Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C497443:Hif1a protein, mouse