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: Nan Lin, Si Chen, Weidong Pan, Linan Xu, Kunpeng Hu, Ruiyun Xu
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 301 Issue 2 Pg. C469-77 (Aug 2011) ISSN: 1522-1563 [Electronic] United States
• PMID: 21543745 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Ccnd1 protein, rat
• Cdkn1a protein, rat
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Cyclin-Dependent Kinase Inhibitor p21
• Indoles
• NP 603
• Propionates
• Protein Kinase Inhibitors
• smooth muscle actin, rat
• Fibroblast Growth Factor 2
• Cyclin D1
• Tyrosine
• Carbon Tetrachloride
• Fgfr1 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 1
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1

Topics

• Actins (metabolism)
• Animals
• Carbon Tetrachloride
• Cell Proliferation (drug effects)
• Cells, Cultured
• Collagen Type I (metabolism)
• Collagen Type I, alpha 1 Chain
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblast Growth Factor 2 (metabolism)
• Hepatic Stellate Cells (drug effects, enzymology, pathology)
• Indoles (pharmacology)
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis, Experimental (chemically induced, enzymology, pathology, prevention & control)
• MAP Kinase Kinase 1 (genetics, metabolism)
• Male
• Phosphorylation
• Propionates (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Tyrosine