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https://hdl.handle.net/2440/63612
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dc.contributor.author | Pishas, K. | - |
dc.contributor.author | Al-ejeh, F. | - |
dc.contributor.author | Zinonos, I. | - |
dc.contributor.author | Kumar, R. | - |
dc.contributor.author | Evdokiou, A. | - |
dc.contributor.author | Brown, M. | - |
dc.contributor.author | Callen, D. | - |
dc.contributor.author | Neilsen, P. | - |
dc.date.issued | 2011 | - |
dc.identifier.citation | Clinical Cancer Research, 2011; 17(3):494-504 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.issn | 1557-3265 | - |
dc.identifier.uri | http://hdl.handle.net/2440/63612 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Kathleen I. Pishas, Fares Al-Ejeh, Irene Zinonos, Raman Kumar, Andreas Evdokiou, Michael P. Brown, David F. Callen, and Paul M. Neilsen | - |
dc.language.iso | en | - |
dc.publisher | American Association for Cancer Research | - |
dc.rights | © 2010 American Association for Cancer Research | - |
dc.source.uri | http://dx.doi.org/10.1158/1078-0432.ccr-10-1587 | - |
dc.subject | Cell Line, Tumor | - |
dc.subject | Humans | - |
dc.subject | Imidazoles | - |
dc.subject | Piperazines | - |
dc.subject | Cell Cycle Proteins | - |
dc.subject | Proto-Oncogene Proteins | - |
dc.subject | Nuclear Proteins | - |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | - |
dc.subject | Apoptosis | - |
dc.subject | Drug Synergism | - |
dc.subject | Genes, p53 | - |
dc.subject | Proto-Oncogene Proteins c-mdm2 | - |
dc.subject | Molecular Targeted Therapy | - |
dc.subject | Sarcoma, Ewing | - |
dc.title | Nutlin-3a is a potential therapeutic for Ewing sarcoma | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-10-1587 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/511303 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Kumar, R. [0000-0001-7976-8386] | - |
dc.identifier.orcid | Evdokiou, A. [0000-0001-8321-9806] | - |
dc.identifier.orcid | Brown, M. [0000-0002-5796-1932] [0000-0002-6678-1407] | - |
dc.identifier.orcid | Callen, D. [0000-0002-6189-9991] | - |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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