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- Title
Vandetanib and ADAM inhibitors synergistically attenuate the pathological migration of EBV-infected retinal pigment epithelial cells by regulating the VEGF-mediated MAPK pathway.
- Authors
DAEJIN KIM; HYUN-SUK KO; GA BIN PARK; DAE YOUNG HUR; YEONG SEOK KIM; JAE WOOK YANG
- Abstract
The extracellular signals induced by vascular endothelial growth factor (VEGF) are implicated in choroidal neovascularization (CNV) and thus, are associated with vision-limiting complications in the human retina. Vandetanib is an oral anticancer drug that selectively inhibits the activities of VEGF receptor and epidermal growth factor receptor tyrosine kinase; however, the effects of vandetanib on VEGF in retinal pigment epithelial (RPE) cells have not yet been studied. In the present study, a combined treatment of vandetanib and a disintegrin and metalloproteinase (ADAM) protein inhibitors were used to assess the regulation of Epstein-Barr virus (EBV)-infected ARPE19 cells (ARPE19/EBV) migration as a model of CNV. Vandetanib suppressed the expression of the mesenchymal markers ADAM10 and ADAM17 in ARPE19/EBV cells, and also upregulated epithelial cell markers of the RPE cells, E-cadherin and N-cadherin. The migratory activity of ARPE19/EBV induced by VEGF was efficiently blocked by vandetanib. Furthermore, co-treatment with vandetanib and an ADAM10 inhibitor (GI254023X) or ADAM17 inhibitor (Marimastat) synergistically prevented migration and the expression of vimentin, Snail and α-smooth muscle actin by regulating extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. These results suggest that a combination treatment of vandetanib and ADAM inhibitors may be developed as a novel therapeutic regimen to control retina neovascular disease.
- Subjects
EXTRACELLULAR matrix; VASCULAR endothelial growth factors; NEOVASCULARIZATION; ANTINEOPLASTIC agents; PROTEIN-tyrosine kinases
- Publication
Experimental & Therapeutic Medicine, 2017, Vol 13, Issue 4, p1415
- ISSN
1792-0981
- Publication type
Article
- DOI
10.3892/etm.2017.4110