Details

Autor(en) / Beteiligte

• Akhmetshina, Alfiya
• Dees, Clara
• Pileckyte, Margarita
• Maurer, Britta
• Axmann, Roland
• Jüngel, Astrid
• Zwerina, Jochen
• Gay, Steffen
• Schett, Georg
• Distler, Oliver
• Distler, Jörg H.W

Titel

Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis

Ist Teil von

• The FASEB journal, 2008-07, Vol.22 (7), p.2214-2222

Ort / Verlag

United States: The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (IC₅₀ 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.