C-kit mutations determine dasatinib mechanism of action in HMC-1 neoplastic mast cells: dasatinib differently regulates PKCδ translocation in HMC-1560 and HMC-1560, 816 cell lines. (16th July 2015)

• Record Type: Journal Article
• Authors: Tobío, Araceli; Alfonso, Amparo; Botana, Luis M.
• Is Part Of: Immunopharmacology and immunotoxicology. Volume 37:Number 4(2015:Aug.)
• Page Start: 380
• Page End: 387
• Publication Date: 2015-07-16
• Subjects: C-kit -- dasatinib -- HMC-1 -- PKC -- PMA; Immunopharmacology -- Periodicals; Immunotoxicology -- Periodicals; Antibody-toxin conjugates -- Periodicals; Immunology -- Periodicals; 615.37
• Languages: English
• ISSNs: 0892-3973

Abstract

Abstract: Purpose : 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. Conclusion : 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.