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Article: Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation

TitleHypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation
Authors
KeywordsChk1/2 activation
Hypoxia-selectivity
Hypoxia-targeting
Nasopharyngeal carcinoma (NPC)
Tirapazamine
Issue Date2011
PublisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997
Citation
Investigational New Drugs, 2011, v. 29 n. 3, p. 401-410 How to Cite?
AbstractHypoxia is commonly developed in solid tumors, which contributes to metastasis as well as radio- and chemo-resistance. Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer prevalent in Southeast Asia with a high incidence rate of 15-30/100,000 persons/year (comparable to that of pancreatic cancer in the US). Previous clinical studies in NPC showed that hypoxia is detected in almost 100% of primary tumors and overexpression of hypoxia markers correlated with poor clinical outcome. Tirapazamine (TPZ) is a synthetic hypoxia-activated prodrug, which preferentially forms cytotoxic and DNA-damaging free radicals under hypoxia, thus selectively eradicate hypoxic cells. Here, we hypothesized that specific hypoxia-targeting by this clinical trial agent may be therapeutic for NPC. Our findings demonstrated that under hypoxia, TPZ was able to induce preferential growth inhibition of NPC cells, which was associated with marked cell cycle arrest at S-phase and PARP cleavage (a hallmark of apoptosis). Examination of S-phase checkpoint regulators revealed that Chk1 and Chk2 were selectively activated by TPZ in NPC cells under hypoxia. Hypoxia-selectivity of TPZ was also demonstrated by preferential downregulation of several important hypoxia-induced markers (HIF-1α, CA IX and VEGF) under hypoxia. Furthermore, we demonstrated that TPZ was equally effective and hypoxia-selective even in the presence of the EBV oncoprotein, LMP1 or the EBV genome. In summary, encouraging results from this proof-of-concept study implicate the therapeutic potential of hypoxia-targeting approaches for the treatment of NPC. © 2009 Springer Science+Business Media, LLC.
Persistent Identifierhttp://hdl.handle.net/10722/124484
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council, Hong Kong GovernmentCUHK4442/06M
Funding Information:

Financial support: Research Grant Council, Hong Kong Government (CUHK4442/06M, to ATC Chan and EP Hui). Result of this study was presented in parts at AACR annual meeting in San Diego, USA, 2008.

References

 

DC FieldValueLanguage
dc.contributor.authorHong, Ben_HK
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorHui, EPen_HK
dc.contributor.authorNg, MHLen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorSung, FLen_HK
dc.contributor.authorTsang, CMen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorChan, ATCen_HK
dc.date.accessioned2010-10-31T10:36:59Z-
dc.date.available2010-10-31T10:36:59Z-
dc.date.issued2011en_HK
dc.identifier.citationInvestigational New Drugs, 2011, v. 29 n. 3, p. 401-410en_HK
dc.identifier.issn0167-6997en_HK
dc.identifier.urihttp://hdl.handle.net/10722/124484-
dc.description.abstractHypoxia is commonly developed in solid tumors, which contributes to metastasis as well as radio- and chemo-resistance. Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer prevalent in Southeast Asia with a high incidence rate of 15-30/100,000 persons/year (comparable to that of pancreatic cancer in the US). Previous clinical studies in NPC showed that hypoxia is detected in almost 100% of primary tumors and overexpression of hypoxia markers correlated with poor clinical outcome. Tirapazamine (TPZ) is a synthetic hypoxia-activated prodrug, which preferentially forms cytotoxic and DNA-damaging free radicals under hypoxia, thus selectively eradicate hypoxic cells. Here, we hypothesized that specific hypoxia-targeting by this clinical trial agent may be therapeutic for NPC. Our findings demonstrated that under hypoxia, TPZ was able to induce preferential growth inhibition of NPC cells, which was associated with marked cell cycle arrest at S-phase and PARP cleavage (a hallmark of apoptosis). Examination of S-phase checkpoint regulators revealed that Chk1 and Chk2 were selectively activated by TPZ in NPC cells under hypoxia. Hypoxia-selectivity of TPZ was also demonstrated by preferential downregulation of several important hypoxia-induced markers (HIF-1α, CA IX and VEGF) under hypoxia. Furthermore, we demonstrated that TPZ was equally effective and hypoxia-selective even in the presence of the EBV oncoprotein, LMP1 or the EBV genome. In summary, encouraging results from this proof-of-concept study implicate the therapeutic potential of hypoxia-targeting approaches for the treatment of NPC. © 2009 Springer Science+Business Media, LLC.en_HK
dc.languageengen_HK
dc.publisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997en_HK
dc.relation.ispartofInvestigational New Drugsen_HK
dc.rightsThe original publication is available at www.springerlink.com-
dc.subjectChk1/2 activationen_HK
dc.subjectHypoxia-selectivityen_HK
dc.subjectHypoxia-targetingen_HK
dc.subjectNasopharyngeal carcinoma (NPC)en_HK
dc.subjectTirapazamineen_HK
dc.titleHypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0167-6997&volume=&spage=&epage=&date=2009&atitle=Hypoxia-targeting+by+tirapazamine+(TPZ)+induces+preferential+growth+inhibition+of+nasopharyngeal+carcinoma+cells+with+Chk1/2+activation-
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s10637-009-9356-zen_HK
dc.identifier.pmid20013349-
dc.identifier.scopuseid_2-s2.0-79955585432en_HK
dc.identifier.hkuros182664en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955585432&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume29en_HK
dc.identifier.issue3en_HK
dc.identifier.spage401en_HK
dc.identifier.epage410en_HK
dc.identifier.isiWOS:000289526400001-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridHong, B=7202125896en_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridHui, EP=7005081895en_HK
dc.identifier.scopusauthoridNg, MHL=35292609300en_HK
dc.identifier.scopusauthoridCheng, SH=7404681588en_HK
dc.identifier.scopusauthoridSung, FL=50562179900en_HK
dc.identifier.scopusauthoridTsang, CM=24831236400en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.citeulike6468449-

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