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 language | English |
|---|---|
| Pages (from-to) | 61-69 |
| Number of pages | 9 |
| Journal | Circulation Research |
| Volume | 100 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2007 |
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Keywords
- Angiogenesis
- Cell cycle
- Endothelial cells
- Signaling pathways
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
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 journal › Article
}
TY - JOUR
T1 - Antiangiogenic activity of the MDM2 antagonist nutlin-3
AU - Secchiero, Paola
AU - Corallini, Federica
AU - Gonelli, Arianna
AU - Dell'Eva, Raffaella
AU - Vitale, Marco
AU - Capitani, Silvano
AU - Albini, Adriana
AU - Zauli, Giorgio
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cell cycle
KW - Endothelial cells
KW - Signaling pathways
UR - http://www.scopus.com/inward/record.url?scp=33846087742&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846087742&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000253975.76198.ff
DO - 10.1161/01.RES.0000253975.76198.ff
M3 - Article
C2 - 17138942
AN - SCOPUS:33846087742
VL - 100
SP - 61
EP - 69
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -