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Dual inhibition of c‐abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis
Author(s) -
Akhmetshina Alfiya,
Dees Clara,
Pileckyte Margarita,
Maurer Britta,
Axmann Roland,
Jüngel Astrid,
Zwerina Jochen,
Gay Steffen,
Schett Georg,
Distler Oliver,
Distler Jörg H. W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-105627
Subject(s) - nilotinib , dasatinib , pharmacology , platelet derived growth factor receptor , medicine , cancer research , tyrosine kinase inhibitor , extracellular matrix , fibrosis , tyrosine kinase , chemistry , growth factor , receptor , cancer , biochemistry
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.—Akhmetshina, A., Dees, C., Pileckyte, M., Maurer, B., Axmann, R., Jüngel, A., Zwerina, J., Gay, S., Schett, G., Distler, O., Distler, J. H. W. Dual inhibition of c‐abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J. 22, 2214–2222 (2008)