Everolimus is a potent inhibitor of activated hepatic stellate cell functions in vitro and in vivo , while demonstrating anti-angiogenic activities

Piguet, Anne Christine; Majumder, Syamantak; Maheshwari, Uma; Manjunathan, Reji; Saran, Uttara; Chatterjee, Suvro; Dufour, Jean-François (2014). Everolimus is a potent inhibitor of activated hepatic stellate cell functions in vitro and in vivo , while demonstrating anti-angiogenic activities. Clinical science, 126(11), pp. 775-784. Portland 10.1042/CS20130081

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Piguet, Anne Christine and Dufour, Jean-François

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0143-5221

Publisher:

Portland

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

10 Oct 2014 16:47

Last Modified:

06 Nov 2015 09:48

Publisher DOI:

10.1042/CS20130081

Uncontrolled Keywords:

angiogenesis, everolimus, hepatic stellate cell, hepatocellular carcinoma, mammalian target of rapamycin (mTOR)

BORIS DOI:

10.7892/boris.53725

URI:

https://boris.unibe.ch/id/eprint/53725

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