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

93 Citations (Scopus)

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

Fingerprint

Endothelial Cells
Doxorubicin
Apoptosis
Coculture Techniques
Cell Cycle
Growth Differentiation Factor 15
Phosphatidylinositol 3-Kinase
p53 Genes
Cell Cycle Checkpoints
nutlin 3
Cell Movement
Fibroblasts
Pharmacology
In Vitro Techniques

Keywords

  • Angiogenesis
  • Cell cycle
  • Endothelial cells
  • Signaling pathways

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Secchiero, P., Corallini, F., Gonelli, A., Dell'Eva, R., Vitale, M., Capitani, S., ... 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

Antiangiogenic activity of the MDM2 antagonist nutlin-3. / Secchiero, Paola; Corallini, Federica; Gonelli, Arianna; Dell'Eva, Raffaella; Vitale, Marco; Capitani, Silvano; Albini, Adriana; Zauli, Giorgio.

In: Circulation Research, Vol. 100, No. 1, 01.2007, p. 61-69.

Research output: Contribution to journalArticle

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, vol. 100, no. 1, pp. 61-69. https://doi.org/10.1161/01.RES.0000253975.76198.ff
Secchiero P, Corallini F, Gonelli A, Dell'Eva R, Vitale M, Capitani S et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circulation Research. 2007 Jan;100(1):61-69. https://doi.org/10.1161/01.RES.0000253975.76198.ff
Secchiero, Paola ; Corallini, Federica ; Gonelli, Arianna ; Dell'Eva, Raffaella ; Vitale, Marco ; Capitani, Silvano ; Albini, Adriana ; Zauli, Giorgio. / Antiangiogenic activity of the MDM2 antagonist nutlin-3. In: Circulation Research. 2007 ; Vol. 100, No. 1. pp. 61-69.
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