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


OBJECTIVE
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.
Economou
Mario A
MA
Cellular and Molecular Tumour Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska R8:04, Karolinska Institute, Stockholm, Sweden. mario-alexander.economou@sankterik.se
Wu
Jiangmei
J
Vasilcanu
Daiana
D
Rosengren
Linda
L
All-Ericsson
Charlotta
C
van der Ploeg
Ingeborg
I
Menu
Eline
E
Girnita
Leonard
L
Axelson
Magnus
M
Larsson
Olle
O
Seregard
Stefan
S
Kvanta
Anders
A
D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D007274:Injections, Intraperitoneal; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010857:Pigment Epithelium of Eye / Q000187:drug effects / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin