New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis

• Published in: Journal of hepatology 2010-07, Vol.53 (1), p.132-144
• Main Authors: Wang, Yan, Gao, Juncha, Zhang, Di, Zhang, Jian, Ma, Junji, Jiang, Huiqing
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Base Sequence; Benzenesulfonates - pharmacology; Biological and medical sciences; Caspase 3 - metabolism; Cell Cycle - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Collagen; Collagen Type I - biosynthesis; Collagen Type I - genetics; DNA Primers - genetics; Down-Regulation - drug effects; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic stellate cell; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Humans; In Vitro Techniques; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; MAP Kinase Signaling System - drug effects; Medical sciences; Niacinamide - analogs & derivatives; Other diseases. Semiology; Phenylurea Compounds; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sorafenib
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.02.027

Background & Aims During the process of liver fibrosis, hepatic stellate cells (HSCs) play a critical role in the excessive production of extracellular matrix (ECM). We evaluated the therapeutic effects of sorafenib, a multiple receptor tyrosine kinase inhibitor, targeting platelet-derived growth factor (PDGF) receptor and the Raf/extracellular-signal-regulated kinase (ERK) signaling pathway, on liver fibrosis and HSC proliferation. Methods The in vivo effects of sorafenib were monitored in the livers of rats with liver fibrosis, and simultaneously proliferation assays, apoptosis induction studies, and collagen synthesis measurement were conducted in vitro in rat and human HSCs and primary HSCs. Results Sorafenib treatment attenuated liver fibrosis and was associated with a significant decrease in intrahepatic fibrogenesis, hydroxyproline accumulation and collagen deposition. Sorafenib reduced HSC proliferation and resulted in significantly higher levels of apoptosis. Moreover, sorafenib downregulated Cyclin D1 and Cyclin-dependent kinase 4 (Cdk-4), simultaneously increased expression of Fas, Fas-L, and Caspase-3, and decreased the ratio of Bcl-2 to Bax. Sorafenib treatment increased the ratio of matrix metalloproteinases (MMPs) to tissue inhibitor of matrix metalloproteinases (TIMPs) and reduced collagen synthesis in HSCs. Sorafenib inhibited the phosphorylation of ERK, Akt and 70-kDa ribosomal S6 kinase (p70S6K), both in vitro and in vivo. Conclusions Sorafenib induces the suppression of collagen accumulation and HSC growth warranting the use of sorafenib as a potential therapeutic agent in the treatment of liver fibrosis.