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.

Paeoniflorin alleviates liver fibrosis by inhibiting HIF-1α through mTOR-dependent pathway

“…HSC activation and ECM genesis. A variety of studies have revealed that mTOR inhibitors can decrease the degree of liver fibrosis via mTOR signaling pathway [35,36]. HIF-1, serving as a mediator of adaptation to hypoxia and pathological response, is a physiological regulator of gene transcription.…”

Cytokine Production and Signaling in Stellate Cells

“…Moreover, PIGF induced proliferation and migration of cultured HSCs via activation of ERK1/2. Another study indicating the role of angiogenesis in the regulation of the fibrogenic process investigated the effects of everolimus, which inhibits collagen production by activated HSCs, as well as their contraction and transition toward an activated status [42]. The mechanism of angiogenesis is also tightly regulated through angiogenesis inhibitors.…”

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

“…Other mTOR inhibitors, sirolimus and everolimus, also reduced fibrosis progression and portal hypertension in BDL rats (Patsenker et al 2011). Moreover, everolimus worked via multiple mechanisms, including inhibiting angiogenesis and preventing the tube formation and migration of liver sinusoidal endothelial cells (Piguet et al 2014). The clinical study using everolimus monotherapy in liver transplantation recipients showed the less serum expression of TGF-β1, but no differences in inflammatory activity, in APRI test, or in liver elastography (Fernandez-Yunquera et al 2014).…”