Attenuation of early liver fibrosis by pharmacological inhibition of smoothened receptor signaling

• Published in: Journal of drug targeting 2012-11, Vol.20 (9), p.770-782
• Main Authors: Pratap, Akshay, Singh, Saurabh, Mundra, Vaibhav, Yang, Ningning, Panakanti, Ravikiran, Eason, James D., Mahato, Ram I.
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; Biological and medical sciences; Caspase 3 - genetics; cyclopamine; Epithelial-Mesenchymal Transition - drug effects; GDC 0049; Gene Expression Regulation - drug effects; General pharmacology; Hedgehog Proteins - antagonists & inhibitors; Hedgehog signaling; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - pathology; liver fibrosis; Liver Function Tests; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Proliferating Cell Nuclear Antigen - metabolism; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - antagonists & inhibitors; Signal Transduction - drug effects; Smoothened Receptor; therapy; Veratrum Alkaloids - pharmacology
• ISSN: 1061-186X; 1029-2330
• DOI: 10.3109/1061186X.2012.719900

Hedgehog (Hh) signaling is involved in the pathogenesis of liver fibrosis. It has been previously shown that Hh-inhibitor cyclopamine (CYA) can reduce liver fibrosis in rats. However, CYA is not stable in vivo, which limits its clinical application. This study compares the antifibrotic potential of two known Hh antagonists, vismodegib (GDC-0449, abbreviated to GDC) and CYA. GDC is a synthetic molecule presently in clinical cancer trials and has been reported to be safe and efficacious. These drugs attenuated early liver fibrosis in common bile duct ligated rats, improved liver function, and prevented hepatic stellate cell (HSC) activation, thereby suppressing epithelial to mesenchymal transition (EMT). While both CYA and GDC increased the number of proliferating cell nuclear antigen positive liver cells in vivo, only CYA increased Caspase-3 expression in HSCs in rat livers, suggesting that while GDC and CYA effectively attenuate early liver fibrosis, their hepatoprotective effects may be mediated through different modes of action. Thus, GDC has the potential to serve as a new therapeutic agent for treating early liver fibrosis.