New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis.
OBJECTIVE
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.
Wang
Yan
Y
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China.
Gao
Juncha
J
Zhang
Di
D
Zhang
Jian
J
Ma
Junji
J
Jiang
Huiqing
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001557:Benzenesulfonates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000077157:Sorafenib
D001557:Benzenesulfonates; D024042:Collagen Type I; D017931:DNA Primers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D053148:Caspase 3