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dc.contributor.authorHolt, Sarah V
dc.contributor.authorBrookes, Karen E
dc.contributor.authorDive, Caroline
dc.contributor.authorMakin, Guy W J
dc.date.accessioned2012-01-09T12:44:29Z
dc.date.available2012-01-09T12:44:29Z
dc.date.issued2011-04
dc.identifier.citationDown-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. 2011, 25 (4):1177-81 Oncol. Rep.en
dc.identifier.issn1791-2431
dc.identifier.pmid21286665
dc.identifier.doi10.3892/or.2011.1167
dc.identifier.urihttp://hdl.handle.net/10541/200911
dc.description.abstractResistance to conventional chemotherapy is a major problem in several paediatric tumours. One explanation for this is that tumour cells are unable to engage apoptosis after cytotoxic drug-induced damage. Inhibitor of apoptosis proteins (IAPs) function by inhibiting both effector (9) and initiator (3 and 7) caspases. Repression of the widely expressed X-linked IAP (XIAP) by RNAi sensitises adult tumour cells to cytotoxics in vitro. Antisense oligonucleotide (ASO)-induced down-regulation of XIAP is effective at inducing cell death and delaying the growth of adult tumour cells as xenografts and these agents are currently in phase II clinical trials. The importance of XIAP in paediatric tumours has not been characterised but high expression correlates with poor survival in childhood AML. We have used the novel XIAP ASO (AEG35156) to evaluate the effects of down-regulation of XIAP in paediatric tumour cells. Here, we show that AEG35156 can down-regulate XIAP in a number of paediatric cell lines including models of osteosarcoma, rhabdomyosarcoma and Ewing's sarcoma. Cell death assays demonstrated a higher proportion of dead cells after XIAP down-regulation by ASO and these cells displayed increased levels of cleaved caspase-3 and cleaved PARP, showing cell death was due to apoptosis. In long-term clonogenic assays, XIAP ASO sensitised 791T osteosarcoma cells to doxorubicin, etoposide and vincristine. The work presented here suggests that AEG35156, as a monotherapy or in combination with cytotoxic agents, may be of benefit in the treatment of paediatric tumours.
dc.language.isoenen
dc.subject.meshAdult
dc.subject.meshAntibiotics, Antineoplastic
dc.subject.meshAntineoplastic Agents, Phytogenic
dc.subject.meshApoptosis
dc.subject.meshBlotting, Western
dc.subject.meshBone Neoplasms
dc.subject.meshChild
dc.subject.meshDoxorubicin
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshEtoposide
dc.subject.meshHumans
dc.subject.meshOligonucleotides
dc.subject.meshOsteosarcoma
dc.subject.meshRhabdomyosarcoma
dc.subject.meshSarcoma, Ewing's
dc.subject.meshTumor Cells, Cultured
dc.subject.meshTumor Stem Cell Assay
dc.subject.meshVincristine
dc.subject.meshX-Linked Inhibitor of Apoptosis Protein
dc.titleDown-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology, Paterson Institute for Cancer Research, Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.en
dc.identifier.journalOncology Reportsen
html.description.abstractResistance to conventional chemotherapy is a major problem in several paediatric tumours. One explanation for this is that tumour cells are unable to engage apoptosis after cytotoxic drug-induced damage. Inhibitor of apoptosis proteins (IAPs) function by inhibiting both effector (9) and initiator (3 and 7) caspases. Repression of the widely expressed X-linked IAP (XIAP) by RNAi sensitises adult tumour cells to cytotoxics in vitro. Antisense oligonucleotide (ASO)-induced down-regulation of XIAP is effective at inducing cell death and delaying the growth of adult tumour cells as xenografts and these agents are currently in phase II clinical trials. The importance of XIAP in paediatric tumours has not been characterised but high expression correlates with poor survival in childhood AML. We have used the novel XIAP ASO (AEG35156) to evaluate the effects of down-regulation of XIAP in paediatric tumour cells. Here, we show that AEG35156 can down-regulate XIAP in a number of paediatric cell lines including models of osteosarcoma, rhabdomyosarcoma and Ewing's sarcoma. Cell death assays demonstrated a higher proportion of dead cells after XIAP down-regulation by ASO and these cells displayed increased levels of cleaved caspase-3 and cleaved PARP, showing cell death was due to apoptosis. In long-term clonogenic assays, XIAP ASO sensitised 791T osteosarcoma cells to doxorubicin, etoposide and vincristine. The work presented here suggests that AEG35156, as a monotherapy or in combination with cytotoxic agents, may be of benefit in the treatment of paediatric tumours.


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