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¹ Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, Maastricht University and University Hospital, Maastricht, the Netherlands; ² The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, Baltimore, Maryland; ³ Free University of Brussels, Faculty of Medicine, Laboratory of Molecular Virology, Brussels, Belgium; and ⁴ Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, Spain

Requests for reprints: Arjan W. Griffioen, Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, Maastricht University and University Hospital, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. Phone: 31-43-3874630; Fax: 31-43-3876613. E-mail: aw.griffioen{at}path.unimaas.nl

Inhibitors of DNA methyltransferases (DNMT) and histone deacetylases can reactivate epigenetically silenced tumor suppressor genes and thereby decrease tumor cell growth. Little, however, is known on the effects of these compounds in endothelial cell biology and tumor angiogenesis. Here, we show that the DNMT inhibitors 5-aza-2'-deoxycytidine and zebularine markedly decrease vessel formation in different tumor models. We show that DNMT inhibitors are antiproliferative for tumor-conditioned endothelial cells, without affecting endothelial cell apoptosis and migration. Furthermore, these compounds inhibit angiogenesis in vitro and in vivo as shown by inhibition of endothelial cells sprouting in a three-dimensional gel and inhibition of microvessel formation in the chorioallantoic membrane, respectively. 5-Aza-2'-deoxycytidine, as well as the histone deacetylase inhibitor trichostatin A, reactivates the growth-inhibiting genes TSP1, JUNB, and IGFBP3, which are suppressed in tumor-conditioned endothelial cells. Despite enhanced DNMT activity and increased overall genomic methylation levels in tumor-conditioned endothelial cells, silencing of these genes seemed not to be regulated by direct promoter hypermethylation. For IGFBP3, gene expression in endothelial cells correlated with histone H3 acetylation patterns. In conclusion, our data show that DNMT inhibitors have angiostatic activity in addition to their inhibitory effects on tumor cells. This dual action of these compounds makes them promising anticancer therapeutics. [Mol Cancer Ther 2006;5(2)467–75]

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Received 10/11/05; revised 11/11/05; accepted 12/ 8/05.

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