title: Anticancer effects of the p53 activator nutlin-3 in Ewing's sarcoma cells.
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.
authors.affiliation: University Children's Hospital Jena, Department of Paediatric Haematology and Oncology, Jena, Germany. juergen.sonnemann@med.uni-jena.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sonnemann
authors.forename: Chithra D
authors.initials: CD
authors.lastname: Palani
authors.forename: Susan
authors.initials: S
authors.lastname: Wittig
authors.forename: Sabine
authors.initials: S
authors.lastname: Becker
authors.forename: Friederike
authors.initials: F
authors.lastname: Eichhorn
authors.forename: Astrid
authors.initials: A
authors.lastname: Voigt
authors.forename: James F
authors.initials: JF
authors.lastname: Beck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005434:Flow Cytometry / Q000379:methods; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D008564:Membrane Potentials; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3