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dc.contributor.authorHussein, Deema
dc.contributor.authorEstlin, Edward J
dc.contributor.authorDive, Caroline
dc.contributor.authorMakin, Guy W J
dc.date.accessioned2009-07-09T12:22:20Z
dc.date.available2009-07-09T12:22:20Z
dc.date.issued2006-09
dc.identifier.citationChronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells. 2006, 5 (9):2241-50 Mol. Cancer Ther.en
dc.identifier.issn1535-7163
dc.identifier.pmid16985058
dc.identifier.doi10.1158/1535-7163.MCT-06-0145
dc.identifier.urihttp://hdl.handle.net/10541/73116
dc.description.abstractHypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature. Direct measurement of low oxygen levels in a range of adult tumor types has correlated tumor hypoxia with advanced stage, poor response to chemotherapy and radiotherapy, and poor prognosis. Little is known about the importance of hypoxia in pediatric tumors; therefore, we evaluated the effects of hypoxia on the response of the neuroblastoma cell lines SH-EP1 and SH-SY5Y to the clinically relevant drugs, vincristine, etoposide, and cisplatin. Short periods of hypoxia (1% O2) of up to 16 hours had no effect on drug-induced apoptosis or clonogenic survival. Prolonged hypoxia of 1 to 7 days leads to reduction in vincristine- and etoposide-induced apoptosis in SH-SY5Y and SH-EP1 cells, and this was reflected in increased clonogenic survival under these conditions. Neither short-term nor prolonged hypoxia had any effect on the clonogenic response to cisplatin in SH-SY5Y cells. Hypoxia-inducible factor-1 (HIF-1) alpha was stabilized in these cell lines within 2 hours of hypoxia but was no longer detectable beyond 48 hours of hypoxia. Up-regulation of carbonic anhydrase IX showed HIF-1alpha to be transcriptionally active. Down-regulation of HIF-1alpha by short hairpin RNA interference and the small-molecule 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole reduced hypoxia-induced drug resistance. These results suggest that prolonged hypoxia leads to resistance to clinically relevant drugs in neuroblastoma and that therapies aimed at inhibiting HIF-1alpha function may be useful in overcoming drug resistance in this tumor.
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subject.meshApoptosis
dc.subject.meshCell Hypoxia
dc.subject.meshCell Line, Tumor
dc.subject.meshCisplatin
dc.subject.meshDown-Regulation
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshEtoposide
dc.subject.meshHumans
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit
dc.subject.meshIndazoles
dc.subject.meshNeuroblastoma
dc.subject.meshProto-Oncogene Proteins c-bcl-2
dc.subject.meshVincristine
dc.titleChronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells.en
dc.typeArticleen
dc.contributor.departmentCellular and Molecular Pharmacology, Paterson Institute for Cancer Research, Royal Manchester Children's Hospital, University of Manchester, Manchester M20 4BX, United Kingdom.en
dc.identifier.journalMolecular Cancer Therapeuticsen
html.description.abstractHypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature. Direct measurement of low oxygen levels in a range of adult tumor types has correlated tumor hypoxia with advanced stage, poor response to chemotherapy and radiotherapy, and poor prognosis. Little is known about the importance of hypoxia in pediatric tumors; therefore, we evaluated the effects of hypoxia on the response of the neuroblastoma cell lines SH-EP1 and SH-SY5Y to the clinically relevant drugs, vincristine, etoposide, and cisplatin. Short periods of hypoxia (1% O2) of up to 16 hours had no effect on drug-induced apoptosis or clonogenic survival. Prolonged hypoxia of 1 to 7 days leads to reduction in vincristine- and etoposide-induced apoptosis in SH-SY5Y and SH-EP1 cells, and this was reflected in increased clonogenic survival under these conditions. Neither short-term nor prolonged hypoxia had any effect on the clonogenic response to cisplatin in SH-SY5Y cells. Hypoxia-inducible factor-1 (HIF-1) alpha was stabilized in these cell lines within 2 hours of hypoxia but was no longer detectable beyond 48 hours of hypoxia. Up-regulation of carbonic anhydrase IX showed HIF-1alpha to be transcriptionally active. Down-regulation of HIF-1alpha by short hairpin RNA interference and the small-molecule 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole reduced hypoxia-induced drug resistance. These results suggest that prolonged hypoxia leads to resistance to clinically relevant drugs in neuroblastoma and that therapies aimed at inhibiting HIF-1alpha function may be useful in overcoming drug resistance in this tumor.


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