title: XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.
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.
authors.affiliation: Sarcoma Research Group, Discipline of Medicine, University of Adelaide, Adelaide, Australia.|Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pishas
authors.affiliation: Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Alaknanda
authors.initials: A
authors.lastname: Adwal
authors.affiliation: Department of Surgery, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Neuhaus
authors.affiliation: Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Clayer
authors.affiliation: Division of Tissue Pathology, SA Pathology, Adelaide, Australia.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Farshid
authors.affiliation: Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.|School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Staudacher
authors.affiliation: Sarcoma Research Group, Discipline of Medicine, University of Adelaide, Adelaide, Australia.|Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy*; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000096:biosynthesis; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000737:chemistry; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D016547:Kinesins / Q000037:antagonists & inhibitors; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010069:Oxadiazoles / Q000494:pharmacology*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D049411:Utrophin / Q000096:biosynthesis
chemical_list: C561599:4-nitrobenzodifuroxan; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D003497:Cyclic N-Oxides; D004268:DNA-Binding Proteins; C110183:EDIL3 protein, human; C102754:GPSM2 protein, human; C468783:H2AX protein, human; C584441:HEG1 protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C410089:KIF20A protein, human; C482775:MDM4 protein, human; C121766:MRE11 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010069:Oxadiazoles; D010793:Phthalazines; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C483599:UTRN protein, human; D049411:Utrophin; C000607970:XI-006; C106354:flotillins; D000076228:MRE11 Homologue Protein; D016547:Kinesins; C531550:olaparib