Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling

Abstract

Background and AimsBrivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.Methods In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.ResultsAfter in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.ConclusionBrivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.

Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats

“…The inhibition of HSC activation may also contribute to the reduction of VEGF expression [26]. Moreover, the inhibition of VEGF expression may also inhibit fibrosis by diminishing HSC activation [6]. A reduction in NO production by the endothelium is considered an important mechanism that results in an increase in intrahepatic resistance in liver cirrhosis [27,28].…”

“…Vascular endothelial growth factor (VEGF), an important proangiogenic factor, plays a crucial role in both intra and extra hepatic circulations. Overexpressed VEGF also accelerates intestinal inflammation [4] and promotes liver fibrosis by regulating monocyte infiltration [5] and HSC activation [6]. Activated HSC enhances the activation of liver sinusoidal endothelial cells by releasing VEGF [7].…”

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

“…PDGF, an important signaling pathways involved in hypoxia associated liver fibrosis and HSC activation and proliferation [49], which are currently developed as new antifibrotic drugs target, and have many breakthroughs, including brivanib and nilotinib [50,51]. Sodium orthovanadate is a PTP inhibitor and a pivotal regulator of profibrotic mechanisms that affect the PDGF pathway [36,52].…”

Overexpression and Clinicopathological Contribution of DcR3 in Bladder Urothelial Carcinoma Tissues

“…The Bcl-2 gene is a proto-oncogene, and it can inhibit the tumor cells apoptosis (Jeon and Yoon, 2012;Kouri et al, 2012;Song et al, 2014). VEGF is a signal protein that stimulates vasculogenesis and angiogenesis (Chuangsuwanich et al, 2014;Nakamura et al, 2014). Ki-67 and PCNA are considered as the classical markers of cell proliferation and are in routine used by pathologists in diagnosis of some malignancies.…”