title: Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis.
abstract: Abelson kinase (c-abl) and platelet-derived growth factor (PDGF) are key players in the pathogenesis of systemic sclerosis (SSc). The aim of the present study was to evaluate the antifibrotic potential of dasatinib and nilotinib, 2 novel inhibitors of c-abl and PDGF, which are well tolerated and have recently been approved. Dasatinib and nilotinib dose-dependently reduced the mRNA and protein levels of extracellular matrix proteins in human stimulated dermal fibroblasts from SSc patients (IC(50) of 0.5-2.0 nM for dasatinib and 0.8-2.5 nM for nilotinib). In a mouse model of bleomycin-induced dermal fibrosis, dasatinib and nilotinib potently reduced the dermal thickness, the number of myofibroblasts, and the collagen content of the skin in a dose-dependent manner at well-tolerated doses. These data indicate that dasatinib and nilotinib potently inhibit the synthesis of extracellular matrix in vitro and in vivo at biologically relevant concentrations. Thus, we provide the first evidence that dasatinib and nilotinib might be promising drugs for the treatment of patients with SSc.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Universitätsstr. 29, 91054 Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Margarita
authors.initials: M
authors.lastname: Pileckyte
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.forename: Roland
authors.initials: R
authors.lastname: Axmann
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001706:Biopsy; D002478:Cells, Cultured; D000069439:Dasatinib; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib; D000069439:Dasatinib