Yuqing Liu1, Zhuo Wang2, Shu Qin Kwong2, Eric Lik Hang Lui3, Scott L Friedman4, Fu Rong Li5, Reni Wing Chi Lam2, Guo Chao Zhang5, Hui Zhang6, Tao Ye7. 1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China. Electronic address: yuqing_liu@hotmail.com. 2. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. 3. Department of Biochemistry, The University of Hong Kong, Hong Kong, China. 4. Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA. 5. Clinical Medical Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen 518020, China. 6. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China. 7. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China. Electronic address: bctaoye@inet.polyu.edu.hk.
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 α-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 PPARγ 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 TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and α-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.
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 α-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 PPARγ 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 TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and α-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.
Authors: Carmel B Nanthakumar; Richard J D Hatley; Seble Lemma; Jack Gauldie; Richard P Marshall; Simon J F Macdonald Journal: Nat Rev Drug Discov Date: 2015-09-04 Impact factor: 84.694