Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/94184
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Type: Journal article
Title: XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
Author: Pishas, K.
Adwal, A.
Neuhaus, S.
Clayer, M.
Farshid, G.
Staudacher, A.
Callen, D.
Citation: Scientific Reports, 2015; 5(1):11465-1-11465-16
Publisher: Nature
Issue Date: 2015
ISSN: 2045-2322
2045-2322
Statement of
Responsibility: 
Kathleen I. Pishas, Alaknanda Adwal, Susan J. Neuhaus, Mark T. Clayer, Gelareh Farshid, Alexander H. Staudacher, David F. Callen
Abstract: 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.
Keywords: Apoptosis; Sarcoma
Description: Corrected by Erratum: XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.Scientific reports, Vol. 5, article number 13328, 2015 Acknowledgments section was incomplete, should read “We thank Dr Paul Neilsen, Dr Jayesh Desai, Professor David Thomas and Professor Stephen Lessnick for study support and Dr Laura Vrbanac and Mrs Sophie Kogoj for technical assistance. This study is dedicated to the memory of Brad Neilsen and Tom Wood. This study was supported by the Australasian Sarcoma Study Group (ASSG) Sarcoma Research Award funded through the Rainbows for Kate Foundation in memory of Tom Wood, ASSG and Kicking Goals For Xav Foundation Sarcoma Research Grant, Florey Medical Research Foundation, and the Channel 7 Children’s Research Foundation. KIP acknowledges financial contributions from the University of Adelaide Florey Medical Research Foundation Clinical Cancer Research Fellowship.”
Rights: 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/
RMID: 0030031201
DOI: 10.1038/srep11465
Appears in Collections:Medicine publications

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