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Article: Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

TitleChemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2
Authors
KeywordsApoptosis
Caspases
Chemotherapy
MnSOD
Ovarian cancer
Issue Date2008
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
Citation
British Journal Of Cancer, 2008, v. 99 n. 2, p. 283-293 How to Cite?
AbstractChemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin- and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer. © 2008 Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/168315
ISSN
2015 Impact Factor: 5.569
2015 SCImago Journal Rankings: 2.939
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYeung, BHYen_HK
dc.contributor.authorWong, KYen_HK
dc.contributor.authorLin, MCen_HK
dc.contributor.authorWong, CKCen_HK
dc.contributor.authorMashima, Ten_HK
dc.contributor.authorTsuruo, Ten_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2012-10-08T03:17:26Z-
dc.date.available2012-10-08T03:17:26Z-
dc.date.issued2008en_HK
dc.identifier.citationBritish Journal Of Cancer, 2008, v. 99 n. 2, p. 283-293en_HK
dc.identifier.issn0007-0920en_HK
dc.identifier.urihttp://hdl.handle.net/10722/168315-
dc.description.abstractChemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin- and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer. © 2008 Cancer Research.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjcen_HK
dc.relation.ispartofBritish Journal of Canceren_HK
dc.subjectApoptosisen_HK
dc.subjectCaspasesen_HK
dc.subjectChemotherapyen_HK
dc.subjectMnSODen_HK
dc.subjectOvarian canceren_HK
dc.subject.meshAntioxidants - Pharmacologyen_US
dc.subject.meshApoptosis - Drug Effects - Physiologyen_US
dc.subject.meshCaspase 9 - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshDoxorubicin - Pharmacologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshMitogen-Activated Protein Kinase 1 - Metabolismen_US
dc.subject.meshMitogen-Activated Protein Kinase 3 - Metabolismen_US
dc.subject.meshOligopeptides - Pharmacologyen_US
dc.subject.meshOvarian Neoplasms - Drug Therapy - Enzymology - Geneticsen_US
dc.subject.meshPaclitaxel - Pharmacologyen_US
dc.subject.meshRna, Small Interfering - Geneticsen_US
dc.subject.meshReactive Oxygen Species - Metabolismen_US
dc.subject.meshSuperoxide Dismutase - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshTransfectionen_US
dc.titleChemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2en_HK
dc.typeArticleen_HK
dc.identifier.emailLin, MC: mcllin@hkucc.hku.hken_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityLin, MC=rp00746en_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/sj.bjc.6604477en_HK
dc.identifier.pmid18594523-
dc.identifier.scopuseid_2-s2.0-48249146576en_HK
dc.identifier.hkuros144169-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-48249146576&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume99en_HK
dc.identifier.issue2en_HK
dc.identifier.spage283en_HK
dc.identifier.epage293en_HK
dc.identifier.isiWOS:000257647700009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridYeung, BHY=24402173100en_HK
dc.identifier.scopusauthoridWong, KY=36151671200en_HK
dc.identifier.scopusauthoridLin, MC=7404816359en_HK
dc.identifier.scopusauthoridWong, CKC=35276549400en_HK
dc.identifier.scopusauthoridMashima, T=7004073034en_HK
dc.identifier.scopusauthoridTsuruo, T=36039795500en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK
dc.identifier.citeulike2974251-

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