Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.
Acta Ophthalmol
; 86 Thesis 4: 42-9, 2008 Nov.
Article
em En
| MEDLINE
| ID: mdl-19032681
ABSTRACT
INTRODUCTION:
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 ANDMETHODS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Podofilotoxina
/
Receptor IGF Tipo 1
/
Neovascularização de Coroide
/
Inibidores da Angiogênese
/
Fator A de Crescimento do Endotélio Vascular
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Acta Ophthalmol
Assunto da revista:
OFTALMOLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Suécia