title: C-kit mutations determine dasatinib mechanism of action in HMC-1 neoplastic mast cells: dasatinib differently regulates PKCδ translocation in HMC-1(560) and HMC-1(560,816) cell lines.
abstract: OBJECTIVE
  The second generation of tyrosine kinase inhibitors is a group of compounds that inhibit c-kit receptor activity and therefore widely used in the treatment of mastocytosis. In this research, the relationship between the mechanism of action of tyrosine kinase inhibitors and protein kinase C is investigated in HMC-1(560) or HMC-1(560,816) cell lines.
  
  
  RESULTS
  From all the tyrosine kinase inhibitors tested, nilotinib is the compound that has the highest cytotoxic effect against HMC-1(560) mast cell line, while midostaurin is the most potent in HMC-1(560,816). Moreover, an increase on histamine release is observed after protein kinase C activation either in HMC-1(560) or HMC-1(560,816) cells. Furthermore, dasatinib increases histamine release in both mast cell lines, which could be related with the secondary reactions previously described in dasatinib-treated patients. Dasatinib also induces Ca(2+)-dependent protein kinase C isoforms translocation from the cytosol to the membrane, whereas protein kinase Cδ is translocated from the cytosol to the nucleus in the HMC-1(560,816) cell line, but not in HMC-1(560) cells.
  
  
  CONCLUSIONS
  Results obtained demonstrate that dasatinib induces an important cytotoxic effect in both HMC-1 cell lines and differently regulates protein kinase Cδ in HMC-1(560) and HMC-1(560,816) cells. Finally, our results confirm that PKCδ is an essential target for dasatinib.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario , Lugo , Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: Tobío
authors.forename: Amparo
authors.initials: A
authors.lastname: Alfonso
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D000069439:Dasatinib / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D009154:Mutation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D051745:Protein Kinase C-delta; D000069439:Dasatinib
keywords: C-kit; HMC-1; PKC; PMA; dasatinib