title: Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds.
abstract: Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds--such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine--in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the alphavbeta3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin alphavbeta3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.
authors.affiliation: The Pharmaceutical Research Institute and Albany College of Pharmacy, 9 Samaritan Road, Albany, NY 12208, USA. mousas@acp.edu
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Laura
authors.initials: L
authors.lastname: O'Connor
authors.forename: Toby G
authors.initials: TG
authors.lastname: Rossman
authors.forename: Eric
authors.initials: E
authors.lastname: Block
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D018053:Arsenites / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply* / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D018036:Selenium Compounds / Q000494:pharmacology*; D017670:Sodium Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C426703:3-(3-(3-(4,5-dihydroimidazol-2-ylamino)propyloxylisoxazol-5-yl)carbonylamino)-2-(phenylsulfonylamino)propionic acid; D043925:Angiogenesis Inducing Agents; D018053:Arsenites; D005419:Flavonoids; D007093:Imidazoles; D018036:Selenium Compounds; D017670:Sodium Compounds; D016222:Fibroblast Growth Factor 2; C017947:sodium arsenite; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one