Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

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 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.

• Authors: Mario A Economou, Jiangmei Wu, Daiana Vasilcanu, Linda Rosengren, Charlotta All-Ericsson, Ingeborg van der Ploeg, Eline Menu, Leonard Girnita, Magnus Axelson, Olle Larsson, Stefan Seregard, Anders Kvanta
• Journal: Acta ophthalmologica (Acta Ophthalmol) Vol. 86 Thesis 4 Pg. 42-9 (Nov 2008) ISSN: 1755-3768 [Electronic] England
• PMID: 19032681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Vascular Endothelial Growth Factor A
• picropodophyllin
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Podophyllotoxin

Topics

• Administration, Oral
• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Blotting, Western
• Cell Line
• Choroid (metabolism)
• Choroidal Neovascularization (etiology, pathology, prevention & control)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Injections, Intraperitoneal
• Insulin-Like Growth Factor I (pharmacology)
• Lasers
• Male
• Mice
• Mice, Inbred C57BL
• Podophyllotoxin (administration & dosage, analogs & derivatives, pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Retinal Pigment Epithelium (cytology, drug effects, metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)