Antifibrotic Activity of Sorafenib in Experimental Hepatic Fibrosis: Refinement of Inhibitory Targets, Dosing, and Window of Efficacy In Vivo

Abstract

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. Aim 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 wks with TAA three times pre 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 adminstration for 8 wks, 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 hours 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. Conclusion 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.

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

“…Mejias et al first reported sorafenib ameliorated portal hypertension, intrahepatic fibrosis, inflammation, and angiogenesis in a cirrhotic rat model (19). Subsequent studies demonstrated sorafenib might reduce HSC proliferation, and inhibit the synthesis of fibrogenesis-related proteins and extracellular matrix (7,20,21). Sorafenib inhibits the KLF6/angiopoietin-1/fibronectin to disrupt the LSEC-HSC interactions, affecting the matrix reconstruction and vascular remodeling (22).…”

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

“…Since ACTA2 was not regulated by FOXF1, implication of the TGF-␤ 1 /SMAD pathway is unlikely. Interactions with the RAF/MEK/ERK pathway may be suspected since the tyrosine kinase inhibitor sorafenib, which primarily targets this pathway, represses COL1 but not ACTA2 expression in hepatic stellate cells (13). Interestingly, another Forkhead protein was shown to alter cell behavior through protein-protein interaction (30).…”

Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis

“…The renin-angiotensin system [26,27], adipokines [28,29], tyrosine kinase receptors [30,31], and nuclear receptors such as peroxisome proliferator-activated receptor (PPAR)-c [32] are representative targets.…”