Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis
Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis
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DOI：
10.1096/fj.07-105627
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Akhmetshina, Alfiya;Dees, Clara;Distler, Joerg H. W.
Abelson 激酶 (c-abl) 和血小板衍生生长因子 (PDGF) 是系统性硬化症 (SSc) 发病机制的关键参与者。本研究的目的是评估达沙替尼和尼罗替尼这两种新型 c-abl 和 PDGF 抑制剂的抗纤维化潜力，这两种抑制剂具有良好的耐受性，并且最近已获得批准。达沙替尼和尼洛替尼剂量依赖性地降低 SSc 患者刺激的人真皮成纤维细胞中细胞外基质蛋白的 mRNA 和蛋白质水平（达沙替尼的 IC50 为 0.5-2.0 nM，尼洛替尼的 IC50 为 0.8-2.5 nM）。在博莱霉素诱导的真皮纤维化小鼠模型中，达沙替尼和尼洛替尼在耐受良好的剂量下，以剂量依赖性方式有效降低真皮厚度、肌成纤维细胞数量和皮肤胶原含量。这些数据表明达沙替尼和尼洛替尼在生物学相关浓度下在体外和体内有效抑制细胞外基质的合成。因此，我们提供了第一个证据表明达沙替尼和尼洛替尼可能是治疗 SSc 患者的有希望的药物。
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.