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

Autor: Jiangmei Wu, Leonard Girnita, Olle Larsson, Daiana Vasilcanu, Anders Kvanta, Magnus Axelson, Stefan Seregard, Eline Menu, Linda Rosengren, Mario A. Economou, Ingeborg van der Ploeg, Charlotta All-Ericsson
Přispěvatelé: Immunology and Microbiology, Hematology
Rok vydání: 2008
Předmět:
Male
Vascular Endothelial Growth Factor A
medicine.medical_specialty
genetic structures
medicine.medical_treatment
Blotting
Western
Cell Culture Techniques
Administration
Oral
Down-Regulation
Angiogenesis Inhibitors
Enzyme-Linked Immunosorbent Assay
Retinal Pigment Epithelium
Biology
Transfection
Cell Line
Receptor
IGF Type 1
Mice
Insulin-like growth factor
chemistry.chemical_compound
In vivo
Internal medicine
medicine
Humans
Animals
Insulin-Like Growth Factor I
Pigment Epithelium of Eye
Receptor
Podophyllotoxin
Choroid
Lasers
Growth factor
General Medicine
Choroidal Neovascularization
eye diseases
Mice
Inbred C57BL
Blot
Vascular endothelial growth factor
Vascular endothelial growth factor A
Disease Models
Animal
Ophthalmology
Endocrinology
Choroidal neovascularization
chemistry
Cancer research
Picropodophyllin
sense organs
medicine.symptom
Injections
Intraperitoneal
Zdroj: Acta Ophthalmologica. 86:42-49
ISSN: 1755-375X
DOI: 10.1111/j.1755-3768.2008.01185.x
Popis: 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 such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. Purpose A prior study has 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 antiangiogenic consequences in a murine CNV model. Methods C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in the choroid and retinal pigment epithelial cells (ARPE-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 a 22% to 32% (P = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroid were significantly reduced. In cultured ARPE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. PPP reduced the level of transcriptional activity of the VEGF promoter. Conclusions PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.
Databáze: OpenAIRE
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