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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:1061-186X
1029-2330
DOI:10.3109/1061186X.2012.719900