Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model.

Abstract

Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.

• Authors: Yuko Tokunaga, Yosuke Osawa, Takahiro Ohtsuki, Yukiko Hayashi, Kenzaburo Yamaji, Daisuke Yamane, Mitsuko Hara, Keisuke Munekata, Kyoko Tsukiyama-Kohara, Tsunekazu Hishima, Soichi Kojima, Kiminori Kimura, Michinori Kohara
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 325 (03 23 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28336942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Enzyme Inhibitors
• ICG 001
• Pyrimidinones
• beta Catenin

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage)
• Cyclic AMP Response Element-Binding Protein (antagonists & inhibitors)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage)
• Hepatitis C, Chronic (complications)
• Histocytochemistry
• Injections, Intraperitoneal
• Liver Cirrhosis (pathology)
• Mice, Transgenic
• Pyrimidinones (administration & dosage)
• Treatment Outcome
• Wnt Signaling Pathway
• beta Catenin (antagonists & inhibitors)