Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/63612
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Type: Journal article
Title: Nutlin-3a is a potential therapeutic for Ewing sarcoma
Author: Pishas, K.
Al-ejeh, F.
Zinonos, I.
Kumar, R.
Evdokiou, A.
Brown, M.
Callen, D.
Neilsen, P.
Citation: Clinical Cancer Research, 2011; 17(3):494-504
Publisher: American Association for Cancer Research
Issue Date: 2011
ISSN: 1078-0432
1557-3265
Statement of
Responsibility: 
Kathleen I. Pishas, Fares Al-Ejeh, Irene Zinonos, Raman Kumar, Andreas Evdokiou, Michael P. Brown, David F. Callen, and Paul M. Neilsen
Abstract: <h4>Purpose</h4>Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist.<h4>Experimental design</h4>The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated.<h4>Results</h4>Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4.<h4>Conclusion</h4>Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease.
Keywords: Cell Line, Tumor
Humans
Imidazoles
Piperazines
Cell Cycle Proteins
Proto-Oncogene Proteins
Nuclear Proteins
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Drug Synergism
Genes, p53
Proto-Oncogene Proteins c-mdm2
Molecular Targeted Therapy
Sarcoma, Ewing
Rights: © 2010 American Association for Cancer Research
DOI: 10.1158/1078-0432.CCR-10-1587
Grant ID: http://purl.org/au-research/grants/nhmrc/511303
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