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

Research output: Contribution to journalArticle

Abstract

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 κB 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.

Original languageEnglish
Pages (from-to)61-69
Number of pages9
JournalCirculation Research
Volume100
Issue number1
DOIs
Publication statusPublished - Jan 2007

Keywords

  • Angiogenesis
  • Cell cycle
  • Endothelial cells
  • Signaling pathways

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Antiangiogenic activity of the MDM2 antagonist nutlin-3'. Together they form a unique fingerprint.

  • Cite this

    Secchiero, P., Corallini, F., Gonelli, A., Dell'Eva, R., Vitale, M., Capitani, S., Albini, A., & Zauli, G. (2007). Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circulation Research, 100(1), 61-69. https://doi.org/10.1161/01.RES.0000253975.76198.ff