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XI-006 induces potent p53-independent apoptosis in Ewing sarcoma

There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity...

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Autores principales: Pishas, Kathleen I., Adwal, Alaknanda, Neuhaus, Susan J., Clayer, Mark T., Farshid, Gelareh, Staudacher, Alexander H., Callen, David F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476092/
https://www.ncbi.nlm.nih.gov/pubmed/26095524
http://dx.doi.org/10.1038/srep11465
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author Pishas, Kathleen I.
Adwal, Alaknanda
Neuhaus, Susan J.
Clayer, Mark T.
Farshid, Gelareh
Staudacher, Alexander H.
Callen, David F.
author_facet Pishas, Kathleen I.
Adwal, Alaknanda
Neuhaus, Susan J.
Clayer, Mark T.
Farshid, Gelareh
Staudacher, Alexander H.
Callen, David F.
author_sort Pishas, Kathleen I.
collection PubMed
description There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099–1.61 μM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.
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spelling pubmed-44760922015-06-24 XI-006 induces potent p53-independent apoptosis in Ewing sarcoma Pishas, Kathleen I. Adwal, Alaknanda Neuhaus, Susan J. Clayer, Mark T. Farshid, Gelareh Staudacher, Alexander H. Callen, David F. Sci Rep Article There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099–1.61 μM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma. Nature Publishing Group 2015-06-22 /pmc/articles/PMC4476092/ /pubmed/26095524 http://dx.doi.org/10.1038/srep11465 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Pishas, Kathleen I.
Adwal, Alaknanda
Neuhaus, Susan J.
Clayer, Mark T.
Farshid, Gelareh
Staudacher, Alexander H.
Callen, David F.
XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title_full XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title_fullStr XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title_full_unstemmed XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title_short XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
title_sort xi-006 induces potent p53-independent apoptosis in ewing sarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476092/
https://www.ncbi.nlm.nih.gov/pubmed/26095524
http://dx.doi.org/10.1038/srep11465
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