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Article: Hyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide
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TitleHyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide
 
AuthorsSun, S1
Lee, D1
Lee, NP1
Pu, JKS1
Wong, STS1
Lui, WM1
Fung, CF1
Leung, GKK1
 
KeywordsApoptosis
Cancer resistance
Cell death
Cell structure
Cell survival
 
Issue Date2012
 
PublisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-594X
 
CitationJournal of Neuro-Oncology, 2012, v. 109 n. 3, p. 467-475 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s11060-012-0923-3
 
AbstractTemozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM.
 
DescriptionSpringer open access article
 
ISSN0167-594X
2012 Impact Factor: 3.115
2012 SCImago Journal Rankings: 1.095
 
DOIhttp://dx.doi.org/10.1007/s11060-012-0923-3
 
PubMed Central IDPMC3434886
 
DC FieldValue
dc.contributor.authorSun, S
 
dc.contributor.authorLee, D
 
dc.contributor.authorLee, NP
 
dc.contributor.authorPu, JKS
 
dc.contributor.authorWong, STS
 
dc.contributor.authorLui, WM
 
dc.contributor.authorFung, CF
 
dc.contributor.authorLeung, GKK
 
dc.date.accessioned2012-08-16T05:59:42Z
 
dc.date.available2012-08-16T05:59:42Z
 
dc.date.issued2012
 
dc.description.abstractTemozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM.
 
dc.description.naturepublished_or_final_version
 
dc.descriptionSpringer open access article
 
dc.identifier.citationJournal of Neuro-Oncology, 2012, v. 109 n. 3, p. 467-475 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s11060-012-0923-3
 
dc.identifier.citeulike10878189
 
dc.identifier.doihttp://dx.doi.org/10.1007/s11060-012-0923-3
 
dc.identifier.epage475
 
dc.identifier.hkuros204719
 
dc.identifier.issn0167-594X
2012 Impact Factor: 3.115
2012 SCImago Journal Rankings: 1.095
 
dc.identifier.issue3
 
dc.identifier.pmcidPMC3434886
 
dc.identifier.pmid22763762
 
dc.identifier.scopuseid_2-s2.0-84866053232
 
dc.identifier.spage467
 
dc.identifier.urihttp://hdl.handle.net/10722/159945
 
dc.identifier.volume109
 
dc.languageeng
 
dc.publisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-594X
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Neuro-Oncology
 
dc.rightsThe original publication is available at www.springerlink.com
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subjectApoptosis
 
dc.subjectCancer resistance
 
dc.subjectCell death
 
dc.subjectCell structure
 
dc.subjectCell survival
 
dc.titleHyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide
 
dc.typeArticle
 
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<contributor.author>Wong, STS</contributor.author>
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<description.abstract>Temozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine