title: Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.
abstract: 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 like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institute, Stockholm, Sweden. mario-alexander.economou@sankterik.se
authors.forename: Mario A
authors.initials: MA
authors.lastname: Economou
authors.forename: Jiangmei
authors.initials: J
authors.lastname: Wu
authors.forename: Daiana
authors.initials: D
authors.lastname: Vasilcanu
authors.forename: Linda
authors.initials: L
authors.lastname: Rosengren
authors.forename: Charlotta
authors.initials: C
authors.lastname: All-Ericsson
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Ploeg
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.forename: Leonard
authors.initials: L
authors.lastname: Girnita
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Seregard
authors.forename: Anders
authors.initials: A
authors.lastname: Kvanta
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007274:Injections, Intraperitoneal; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007834:Lasers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin