title: NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats.
abstract: Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.
authors.affiliation: Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, GuangZhou, Peoples Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.forename: Linan
authors.initials: L
authors.lastname: Xu
authors.forename: Kunpeng
authors.initials: K
authors.lastname: Hu
authors.forename: Ruiyun
authors.initials: R
authors.lastname: Xu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine
chemical_list: D000199:Actins; D002251:Carbon Tetrachloride; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D007211:Indoles; D048369:MAP Kinase Kinase 1; D011422:Propionates; D047428:Protein Kinase Inhibitors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D014443:Tyrosine; C530106:Ccnd1 protein, rat; C493958:Cdkn1a protein, rat; C561467:NP 603; C498862:Acta2 protein, rat; C496349:Fgfr1 protein, mouse