Antifibrotic activity of sorafenib in experimental hepatic fibrosis: refinement of inhibitory targets, dosing, and window of efficacy in vivo.
BACKGROUND
Sorafenib, which is approved for treatment of HCC, has also shown promising antifibrotic activity, and therefore refinement of its dosing requirements and window of efficacy are important goals prior to antifibrotic clinical trials.


OBJECTIVE
The purpose of this study was to determine the minimal effective dose and optimal timing of sorafenib therapy in cultured human stellate cells and in rats with experimental hepatic fibrosis.


METHODS
Effects of sorafenib were assessed in a human stellate cell line (LX-2). In vivo, rats were treated for 8 weeks with TAA three times per week (150 mg/kg IP), and with either PBS or sorafenib administered daily at doses of 1.25, 5 or 7 mg/kg/day gavage either at the beginning of TAA administration for 8 weeks, during weeks 4-8, or from weeks 8-12.


RESULTS
Sorafenib treatment significantly inhibited LX-2 proliferation by >75% (7.5 or 15 μM). Treatment with 7.5-μM sorafenib for 12 h markedly inhibited expression of TGFβ1, TIMP-1, collagen I, and MMP2 mRNAs, but not of β-PDGFR or type I TGFβR. In vivo, sorafenib significantly inhibited liver fibrosis when started concurrently with TAA and during weeks 4-8 with TAA. In contrast, there was no significant effect of sorafenib on fibrogenic gene expression or fibrosis when begun after cirrhosis was already established.


CONCLUSIONS
Sorafenib is anti-proliferative and antifibrotic towards human HSCs in culture, and is a potent antifibrotic agent in TAA-induced hepatic fibrosis in rats. The drug is effective at relatively low doses at the early stage of liver fibrosis, but is not effective when cirrhosis is already established.
Division of Liver Diseases, Mount Sinai School of Medicine, Box 1123, 1425 Madison Ave., Room 1170C, New York, NY 10029, USA.
Feng
F
Hong
Hsini
H
Chou
Maria Isabel
MI
Fiel
Scott L
SL
Friedman
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D013853:Thioacetamide / Q000633:toxicity
D010671:Phenylurea Compounds; D013853:Thioacetamide; D009536:Niacinamide; D012313:RNA; D000077157:Sorafenib