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(Circulation Research. 2007;100:61.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3

Paola Secchiero, Federica Corallini, Arianna Gonelli, Raffaella Dell’Eva, Marco Vitale, Silvano Capitani, Adriana Albini, Giorgio Zauli

From the Department of Morphology and Embryology (P.S., F.C., A.G., S.C.), Human Anatomy Section, University of Ferrara; Molecular Oncology Laboratory (R.D.’E.), National Institute for Cancer Research, Genova; Department of Anatomy (M.V.), Pharmacology & Forensic Medicine, University of Parma; IRCCS Multimedica (A.A.), Polo Scientifico e Tecnologico, Milano; and Interdipartimental Center of Molecular Medicine (G.Z.), University of Trieste, Italy.

Correspondence to Paola Secchiero, Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. E-mail secchier{at}mail.umbi.umd.edu

Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 µmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 µmol/L). However, treatment with pharmacological inhibitors of the nuclear factor B and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3–induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in vitro effect of nutlin-3 was its strong antimigratory activity observed at concentrations significantly lower (0.1 µmol/L) than those required to inhibit endothelial cell cycle progression. Taken together, our data suggest that the antiangiogenic activity of nutlin-3 observed in vivo was mainly attributable to inhibition of endothelial cell migration, to some extent attributable to cell cycle arrest, and to a lesser extent attributable to induction of apoptosis.

Key Words: angiogenesis • endothelial cells • cell cycle • signaling pathways

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