Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling

Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian Walters, Lewis Rowland Roberts

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background and Aims: Brivanib 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 (CCl 4), 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. Results: After 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. Conclusion: Brivanib 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.

Original languageEnglish (US)
Article numbere92273
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 7 2014

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platelet-derived growth factor
liver cirrhosis
Platelet-Derived Growth Factor
Liver
Vascular Endothelial Growth Factor A
Liver Cirrhosis
Fibrosis
Chemical activation
Hepatic Stellate Cells
vascular endothelial growth factor receptors
cells
Thioacetamide
liver
bile ducts
Fibroblast Growth Factor Receptors
Vascular Endothelial Growth Factor Receptor
Bile Ducts
Ligation
animal models
Ducts

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. / Nakamura, Ikuo; Zakharia, Kais; Banini, Bubu A.; Mikhail, Dalia S.; Kim, Tae Hyo; Yang, Ju Dong; Moser, Catherine D.; Shaleh, Hassan M.; Thornburgh, Sarah R.; Walters, Ian; Roberts, Lewis Rowland.

In: PLoS One, Vol. 9, No. 4, e92273, 07.04.2014.

Research output: Contribution to journalArticle

Nakamura, I, Zakharia, K, Banini, BA, Mikhail, DS, Kim, TH, Yang, JD, Moser, CD, Shaleh, HM, Thornburgh, SR, Walters, I & Roberts, LR 2014, 'Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling', PLoS One, vol. 9, no. 4, e92273. https://doi.org/10.1371/journal.pone.0092273
Nakamura, Ikuo ; Zakharia, Kais ; Banini, Bubu A. ; Mikhail, Dalia S. ; Kim, Tae Hyo ; Yang, Ju Dong ; Moser, Catherine D. ; Shaleh, Hassan M. ; Thornburgh, Sarah R. ; Walters, Ian ; Roberts, Lewis Rowland. / Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. In: PLoS One. 2014 ; Vol. 9, No. 4.
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AU - Nakamura, Ikuo

AU - Zakharia, Kais

AU - Banini, Bubu A.

AU - Mikhail, Dalia S.

AU - Kim, Tae Hyo

AU - Yang, Ju Dong

AU - Moser, Catherine D.

AU - Shaleh, Hassan M.

AU - Thornburgh, Sarah R.

AU - Walters, Ian

AU - Roberts, Lewis Rowland

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