Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib
Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib
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DOI：
10.1016/j.jhep.2010.11.035
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发表时间：
2011-09-01
影响因子：
25.7
通讯作者：
Ye, Tao
中科院分区：
文献类型：
--
作者：
Liu, Yuqing;Wang, Zhuo;Ye, Tao
背景与目的：尼洛替尼是一种新型的Bcr-Abl等酪氨酸激酶抑制剂。在这项研究中，我们已经研究了它的活性作为一种抗纤维化agent.Methods：尼洛替尼对大鼠和人类HSC的体外效果进行了评估，使用增殖试验和蛋白质印迹。在CCl 4和胆管结扎（BDL）诱导的肝纤维化小鼠中评估尼洛替尼的体内抗纤维化功效。结果：尼洛替尼抑制活化的HSCs的增殖、迁移和肌动蛋白丝形成，以及α-SMA和胶原蛋白的表达。尼洛替尼诱导HSC凋亡，这与bcl-2表达减少、p53表达增加、PARP裂解以及PPAR γ和TRAIL-R表达增加相关。尼洛替尼还诱导细胞周期阻滞，伴随p27表达增加和细胞周期蛋白D1下调。有趣的是，尼洛替尼不仅抑制PDGFR的活化，还通过Src抑制TGFRII的活化。尼洛替尼显著抑制PDGF和TGF β模拟的ERK和Akt磷酸化。此外，尼洛替尼可抑制人HSC中PDGF和TGF β激活的Abl磷酸化形式。在体内，尼洛替尼减少了CCl 4和BDL诱导的纤维化中的胶原沉积和α-SMA表达。这些有益作用与抑制前胶原-（I）、TIMP-1、CD 31、CD 34、VEGF和VEGFR的表达相关。尼洛替尼在体内可诱导HSC发生凋亡，这与bcl-2的下调有关。我们还观察到尼洛替尼处理的CCl 4和BDL肝脏中磷酸化ERK、Akt和Abl的表达降低。除了它的抗纤维化活性，药物是肝保护和降低ALT和AST的升高后，CCl 4和BDL.Conclusions：这些研究揭示了一种新的作用Bcr-Abl活性在治疗肝纤维化通过多种机制，并表明尼洛替尼是一种潜在的有效的抗纤维化剂。(C)2011年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Nilotinib is a novel tyrosine kinase inhibitor of Bcr-Abl and other kinases. In this study, we have examined its activity as an anti-fibrotic agent.Methods: The in vitro effect of Nilotinib on rat and human HSCs was assessed using proliferation assays and Western blotting. The in vivo antifibrotic efficacy of Nilotinib was assessed in mice with liver fibrosis induced by CCl4 and bile duct ligation (BDL).Results: Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of alpha-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs, which was correlated with reduced bcl-2 expression, increased p53 expression, cleavage of PARP, as well as increased expression of PPAR gamma and TRAIL-R. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibited activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibited PDGF and TGF beta-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGF beta-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and alpha-SMA expression in CCl4 and BDL-induced fibrosis. These beneficial effects were associated with suppressed expression of procollagen-(I), TIMP-1, CD31, CD34, VEGF, and VEGFR. Nilotinib could induce HSC undergoing apoptosis in vivo, which was correlated with downregulation of bcl-2. We also observed reduced expression of phosphorylated ERK, Akt, and Abl in the Nilotinib-treated CCl4 and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl4 and BDL.Conclusions: These studies uncover a novel role of Bcr-Abl activity in treatment of liver fibrosis through multiple mechanisms and indicate that Nilotinib represents a potentially effective antifibrotic agent. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.