title: Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition.
abstract: BACKGROUND
  Advances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance. The involvement of BRAFV600E in metabolic reprogramming of melanoma cells provides a rationale for co-targeting metabolism as a therapeutic approach.
  
  
  METHODS
  We examined the effects of dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, on the growth and metabolic activity of human melanoma cell lines. The combined effect of DCA and the BRAF inhibitor vemurafenib was investigated in BRAFV600E -mutated melanoma cell lines. Vemurafenib-resistant cell lines were established in vitro and their sensitivity to DCA was tested.
  
  
  RESULTS
  DCA induced a reduction in glycolytic activity and intracellular ATP levels, and inhibited cellular growth. Co-treatment of BRAFV600E-mutant melanoma cells with DCA and vemurafenib induced a greater reduction in intracellular ATP levels and cellular growth than either compound alone. In addition, melanoma cells with in vitro acquired resistance to vemurafenib retained their sensitivity to DCA.
  
  
  CONCLUSIONS
  These results suggest that DCA potentiates the effect of vemurafenib through a cooperative attenuation of energy production. Furthermore, the demonstration of retained sensitivity to DCA in melanoma cells with acquired resistance to vemurafenib could have implications for melanoma treatment.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Abildgaard
authors.forename: Christina
authors.initials: C
authors.lastname: Dahl
authors.forename: Astrid L
authors.initials: AL
authors.lastname: Basse
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark. perg@cancer.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014633:Valine / Q000235:genetics; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D018698:Glutamic Acid; D003999:Dichloroacetic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014633:Valine