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.

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