title: IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo.
abstract: In the course of a blind screening program for inhibitors of angiogenesis, IB05204 (4,8-dichloro-12-phenylpyrido[5',6':4'',5'';3',2':4,5]dithieno[3'',2''-d':3,2-d]-1,2,3-ditriazine) was selected for its ability to inhibit endothelial tubule-like network formation on Matrigel. IB05204 inhibits the in vivo angiogenesis in the chorioallantoic membrane (CAM) and the mouse Matrigel plug assays. Antiangiogenic activity seems to be highly dependent on the chloro substituents because their removal results in a complete loss of the in vitro inhibitory activity of endothelial differentiation and in vivo antiangiogenic activity in CAM assay. Although IB05204 inhibits the growth of endothelial and tumor cells in culture, its antiangiogenic activity seems to be mainly dependent on the prevention of endothelial capillary-like tube formation and inhibition of endothelial migration because these effects are recorded at lower concentrations. IB05204 treatment inhibits matrix metalloproteinase-2 (MMP-2) production in endothelial and tumor cells, down-regulates endothelial cyclooxygenase-2 expression, and represses phosphorylation of endothelial Akt in response to serum stimulation, suggesting that IB05204 interferes with molecular mechanisms of cell migration and survival. IB05204 induces apoptosis in endothelial cells through cytochrome c release and caspase activation. Data here shown altogether indicate that IB05204 is a compound that interferes with several key steps of angiogenesis, making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies.
authors.affiliation: Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071 Málaga, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martínez-Poveda
authors.forename: Ramón
authors.initials: R
authors.lastname: Muñoz-Chápuli
authors.forename: Salvador
authors.initials: S
authors.lastname: Rodríguez-Nieto
authors.forename: José M
authors.initials: JM
authors.lastname: Quintela
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Medina
authors.forename: Ana R
authors.initials: AR
authors.lastname: Quesada
mesh_terms: D000482:Allantois / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects; D005354:Fibrosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011509:Proteoglycans / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; C526333:IB05204; D007797:Laminin; D011509:Proteoglycans; D014227:Triazines; C059485:matrigel; D003094:Collagen; D020169:Caspases; D020778:Matrix Metalloproteinase 2