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

详细信息    查看全文

• 作者：Jü ; rgen Sonnemann ; ^a ; ^{juergen.sonnemann@med.uni-jena.de"" rel=""nofollow} ; Chithra D. Palani^a ; Susan Wittig^a ; Sabine Becker^a ; Friederike Eichhorn^a ; Astrid Voigt^a ; James F. Beck^a
• 关键词：Ewing&#x2019 ; s sarcoma ; p53 ; Nutlin-3 ; Apoptosis ; Cellular senescence ; NF-κ ; B
• 刊名：European Journal of Cancer
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：47
• 期：9
• 页码：1432-1441
• 全文大小：394 K

文摘

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.