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Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin‐like growth factor‐1 receptor
Author(s) -
Economou Mario A.,
Wu Jiangmei,
Vasilcanu Daiana,
Rosengren Linda,
AllEricsson Charlotta,
Van Der Ploeg Ingeborg,
Menu Eline,
Girnita Leonard,
Axelson Magnus,
Larsson Olle,
Seregard Stefan,
Kvanta Anders
Publication year - 2008
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2008.01185.x
Subject(s) - choroidal neovascularization , vascular endothelial growth factor , in vivo , growth factor , neovascularization , endocrinology , angiogenesis , insulin like growth factor , kinase insert domain receptor , cancer research , medicine , biology , western blot , downregulation and upregulation , receptor , vascular endothelial growth factor a , macular degeneration , ophthalmology , gene , vegf receptors , genetics
Choroidal neovascularization (CNV) is a debilitating complication of age‐related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin‐like growth factor (IGF‐1) and its receptor, IGF‐1R, have been implicated in CNV. Purpose: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin‐like growth factor‐1 receptor (IGF‐1R) activity and causes cell death in uveal melanoma cell lines and in an in‐vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti‐angiogenic consequences in a murine CNV model. Materials and Methods: C57BL/6J mice with laser‐induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE‐19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. Results: Mice treated with PPP, administered intraperitoneally or orally, showed 22–32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE‐19 cells, IGF‐1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. Conclusions: PPP reduces IGF‐1 dependent VEGF expression and CNV in vivo . Accordingly, IGF‐1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.