title: Everolimus is a potent inhibitor of activated hepatic stellate cell functions in vitro and in vivo, while demonstrating anti-angiogenic activities.
abstract: Progression of liver fibrosis to HCC (hepatocellular carcinoma) is a very complex process which involves several pathological phenomena, including hepatic stellate cell activation, inflammation, fibrosis and angiogenesis. Therefore inhibiting multiple pathological processes using a single drug can be an effective choice to curb the progression of HCC. In the present study, we used the mTOR inhibitor everolimus to observe its effect on the in vitro activation of hepatic stellate cells and angiogenesis. The results of the present study demonstrated that everolimus treatment blocked the functions of the immortalized human activated hepatic stellate cell line LX-2 without affecting the viability and migration of primary human stellate cells. We also observed that treatment with everolimus (20 nM) inhibited collagen production by activated stellate cells, as well as cell contraction. Everolimus treatment was also able to attenuate the activation of primary stellate cells to their activated form. Angiogenesis studies showed that everolimus blocked angiogenesis in a rat aortic ring assay and inhibited the tube formation and migration of liver sinusoidal endothelial cells. Finally, everolimus treatment reduced the load of tumoral myofibroblasts in a rat model of HCC. These data suggest that everolimus targets multiple mechanisms, making it a potent blocker of the progression of HCC from liver fibrosis.
authors.affiliation: *Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.affiliation: †Vascular Biology Laboratory, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors.forename: Syamantak
authors.initials: S
authors.lastname: Majumder
authors.affiliation: †Vascular Biology Laboratory, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors.forename: Uma
authors.initials: U
authors.lastname: Maheshwari
authors.affiliation: †Vascular Biology Laboratory, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors.forename: Reji
authors.initials: R
authors.lastname: Manjunathan
authors.affiliation: †Vascular Biology Laboratory, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors.forename: Uttara
authors.initials: U
authors.lastname: Saran
authors.affiliation: †Vascular Biology Laboratory, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors.forename: Suvro
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
mesh_terms: D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000199:Actins; D020533:Angiogenesis Inhibitors; D007166:Immunosuppressive Agents; D003094:Collagen; D000068338:Everolimus; D020123:Sirolimus