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
2011 Impact Factor: 3.214
2011 SCImago Journal Rankings: 0.253
DOIhttp://dx.doi.org/10.1007/s11060-012-0923-3
PubMed Central IDPMC3434886
DC Field
Value
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
2011 Impact Factor: 3.214
2011 SCImago Journal Rankings: 0.253
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
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine