title: Anti-angiogenic activities of hypericin in vivo: potential for ophthalmologic applications.
abstract: Hypericin, a perihydroxylated dianthraquinone is shown here to be a highly potent inhibitor of angiogenesis in several ocular models examined in rat eyes. Extensive angiogenesis induced in the cornea and iris by intra-ocular administration of FGF-2 was effectively inhibited by a minimum of four dose regimens of hypericin (2 mg/kg) administered via the intraperitoneal route at 48 h intervals. Maximal inhibition was achieved when animal treatment with hypericin was initiated 48 h prior to inoculation of FGF-2. The molecular basis for the hypericin-mediated inhibition of angiogenesis in the anterior eye compartment appears to involve several sites in the cascade leading to angiogenesis. We show that the activating phosphorylation of extracellular signal-regulated MAP kinases (ERK1/2) is inhibited by hypericin in human retinal pigment epithelial cells and in EA.hy926 cells, an endothelial hybridoma expressing endothelial cell properties. ERK1/2 activity is required for the transactivation of hypoxia-inducible factor 1 alpha (HIF-1alpha) and in VEGF-induced blood vessel sprouting. MT1-MMP activity in human microvascular endothelial cells was also inhibited. The findings identify hypericin as a potentially useful agent in the treatment of ophthalmic neovascularization pathogeneses.
authors.affiliation: Institute of Hematology & Blood Transfusion Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel. gad.lavie@sheba.health.gov.il
authors.forename: Gad
authors.initials: G
authors.lastname: Lavie
authors.forename: Mathilda
authors.initials: M
authors.lastname: Mandel
authors.forename: Sadick
authors.initials: S
authors.lastname: Hazan
authors.forename: Tilda
authors.initials: T
authors.lastname: Barliya
authors.forename: Michael
authors.initials: M
authors.lastname: Blank
authors.forename: Aaron
authors.initials: A
authors.lastname: Grunbaum
authors.forename: Daniel
authors.initials: D
authors.lastname: Meruelo
authors.forename: Arieh
authors.initials: A
authors.lastname: Solomon
mesh_terms: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000873:Anthracenes; D003315:Cornea / Q000098:blood supply; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2; D016147:Genes, Tumor Suppressor; D006801:Humans; D007498:Iris / Q000098:blood supply; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000873:Anthracenes; C403503:FAM107A protein, human; D009687:Nuclear Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D010569:Perylene; C004965:hypericin; D048049:Extracellular Signal-Regulated MAP Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases