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Research Articles: Therapeutics, Targets, and Development

IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo

¹ Departamento de Biología Molecular y Bioquímica and ² Departamento de Biología Animal, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain; ³ Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden; ⁴ Departamento de Quimica Fundamental, Facultad de Ciencias, Universidad de la Coruña, La Coruña, Spain; and ⁵ Instituto Biomar S.A. Políg. Ind., edificio CEI, Onzonilla, León, Spain

Requests for reprints: Ana R. Quesada, Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071 Málaga, Spain. Phone: 349-52137128; Fax: 349-52132000. E-mail: quesada{at}uma.es

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. [Mol Cancer Ther 2007;6(10):2675–85]

Grant support: PTR1995-0904 and CTQ2006-15279-C03-03 (Ministerio de Educación y Ciencia, Spain).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/27/07; revised 7/ 9/07; accepted 9/ 4/07.