Anticancer effects of the p53 activator nutlin-3 in Ewing's sarcoma cells

Jürgen Sonnemann, Chithra D. Palani, Susan Wittig, Sabine Becker, Friederike Eichhorn, Astrid Voigt, James F. Beck

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Mutation of p53 is rare in Ewing's sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES. The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis. In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3. We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53. Consistently, nutlin-3 elicited apoptosis only in wild-type p53 cells, as assessed by caspase-3 activity assay and flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation. In addition, we found nutlin-3 to evoke cellular senescence, indicating that nutlin-3 induces pleiotropic anticancer effects in ES. Furthermore, combined treatment with nutlin-3 and an inhibitor of NF-κB produced synergistic antineoplastic activity in ES cells. Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES.

Original languageEnglish (US)
Pages (from-to)1432-1441
Number of pages10
JournalEuropean Journal of Cancer
Volume47
Issue number9
DOIs
StatePublished - Jun 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Cellular senescence
  • Ewing's sarcoma
  • NF-κB
  • Nutlin-3
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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