title: Anti-angiogenic activity of arachidonic acid metabolism inhibitors in angiogenesis model systems involving human microvascular endothelial cells and neovascularization in mice.
abstract: We have established an in vitro angiogenesis model using human omental microvascular endothelial (HOME) cells, in which epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulated cell migration and tube formation. In this study, we examined whether alpha-guaiaconic acid (GR-12) and its synthetic 20 derivatives showed inhibition of cell migration and tubular formation of HOME cells. We found that GR-12 inhibits arachidonic acid metabolism, while GR-12 and one derivative, GS-01, inhibit tubular formation of endothelial cells in our model system. Confluent monolayers of HOME cells were damaged with a razor blade and incubated with or without TGF-alpha; HOME cell migration was stimulated about 1.5-fold over control values in the presence of TGF-alpha. Treatment of HOME cells with GR-12 or GS-01 inhibited both spontaneous and TGF-alpha-stimulated migration. GR-12 or GS-01 inhibited TGF-alpha-induced HOME-cell tube formation in type-1 collagen gels. We examined whether these compounds could modulate tubular formation of HOME cells induced by human cancer cells. Enhanced tube formation of HOME cells by co-cultured esophageal cancer cells was almost completely inhibited by co-administration of GR-12 or GS-01. Both compounds also inhibited formation of tubular networks of HOME cells on Matrigels. We also examined anti-angiogenic activity of these compounds in an in vivo model system of tumor angiogenesis in mice. In this system, GS-01 inhibited development of capillary networks at a rate comparable to that of a well-known anti-angiogenic compound, fumagillin, but GR-12 did not. The inhibitor of arachidonic acid metabolism is thus expected to modulate tumor angiogenesis.
authors.affiliation: Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Tomita
authors.forename: A
authors.initials: A
authors.lastname: Morimoto
authors.forename: K
authors.initials: K
authors.lastname: Kohno
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Ono
authors.forename: A
authors.initials: A
authors.lastname: Sugenoya
authors.forename: T
authors.initials: T
authors.lastname: Nishihira
authors.forename: M
authors.initials: M
authors.lastname: Kuwano
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes; D004727:Endothelium; D004938:Esophageal Neoplasms; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008833:Microcirculation; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D009852:Omentum / Q000098:blood supply; D010636:Phenols / Q000494:pharmacology*; D012717:Sesquiterpenes; D014407:Tumor Cells, Cultured
chemical_list: D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D005663:Furans; D010636:Phenols; D012717:Sesquiterpenes; C083771:alpha-guaiaconic acid; D016718:Arachidonic Acid; C026211:fumagillin