Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/14598
Title: Inhibition of PDGF, TGF-beta, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib
Authors: Liu, Y
Wang, Z
Kwong, SQ
Lui, ELH
Friedman, SL
Li, FR
Lam, RWC
Zhang, GC
Zhang, H
Ye, T 
Keywords: Abl
Hepatic stellate cells
Liver fibrosis
Nilotinib
PDGF
TGF-beta 1
Issue Date: 2011
Publisher: Elsevier Science Bv
Source: Journal of hepatology, 2011, v. 55, no. 3, p. 612-625 How to cite?
Journal: Journal of Hepatology 
Abstract: 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 CCl(4) 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 CCl(4) 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 CCl(4) and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl(4) 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.
URI: http://hdl.handle.net/10397/14598
ISSN: 0168-8278
DOI: 10.1016/j.jhep.2010.11.035
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