The cAMP-response element-binding protein-binding protein (CBP)/β-catenin-mediated transcription is essential for cell proliferation and non-differentiation, and is implicated in liver fibrosis. C-82 (the active form of PRI-724) is a second-generation CBP/β-catenin antagonist that inhibits the binding between CBP and β-catenin and increases the binding between β-catenin and p300. C-82 at a concentration of 10μM inhibited the β-catenin signaling in isolated mouse primary quiescent hepatic stellate cells (HSCs) during activation, while the removal of C-82 rapidly restored the features of HSC activation. C-82 treatment also inhibited most gene upregulation induced by HSC activation. Three-day treatment with C-82 (10μM) decreased the mRNA expression of fibrosis-related makers in activated HSCs. Cells started to death seven days following C-82 administration. C-82 treatment also decreased the mRNA expression of survivin, a factor that protects fibroblasts from apoptosis, in activated HSCs. However, C-82 did not induce cell death in quiescent HSCs for at least 15 days. Co-administration of PRI-724 (0.4mg/mouse, four times a week) for 4 weeks reduced CCL4-induced liver fibrosis in C57BL/6 male mice (6 – 9 month-old).[1]
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