title: The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro.
abstract: The Warburg effect describes the ability of cancer cells to produce energy via aerobic glycolysis instead of oxidative phosphorylation of pyruvate. This deviation in mitochondrial metabolism inhibits apoptosis, allowing increased proliferation under conditions of reduced oxygen levels. Dichloroacetate (DCA) was successfully used in several human cancer cell lines to reactivate oxidative phosphorylation in mitochondria. The aim of this study was the characterization and response of canine cancer cell lines after DCA exposure. The effect of 10 mM DCA was characterized in vitro on a set of six canine prostate adenocarcinoma and transitional cell carcinoma (TCC) derived cell lines. Cell counts, lactate levels, apoptosis, expression of apoptotic proteins, survival factors and different miRNAs were analyzed. Additionally, metabolic activity, mitochondrial activity and proliferation were investigated. DCA significantly decreased cell number of all but one utilized cell lines and leads to a significant reduction of lactate release. Decreased survivin levels were found in all cell lines, two of which presented a significant reduction in metabolic activity. Increased miR-375 levels were measured in all TCC cell lines. Reactivation of pyruvate dehydrogenase and an elevated mitochondrial activity appear to induce the transition from aerobic glycolysis back to oxidative phosphorylation. Further, these results display that DCA treatment has a suppressant effect on proliferation of canine cancer cells.
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Harting
authors.affiliation: Evotec AG, D-22419 Hamburg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Stubbendorff
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Willenbrock
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Institute of Biophysics, Leibniz University, D-30419 Hannover, Germany.
authors.forename: Patrik
authors.initials: P
authors.lastname: Schadzek
authors.affiliation: Institute of Biophysics, Leibniz University, D-30419 Hannover, Germany.
authors.forename: Anaclet
authors.initials: A
authors.lastname: Ngezahayo
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
authors.forename: Hugo
authors.initials: HM
authors.lastname: Murua Escobar
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Nolte
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004285:Dogs; D006019:Glycolysis / Q000187:drug effects*; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D035683:MicroRNAs; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D017346:Protein Serine-Threonine Kinases