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Article: Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells

TitleAnti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells
Authors
KeywordsAnoikis-sensitization
Anti-invasion
Lapatinib
NPC
Issue Date2010
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, 2010, p. 1-12 How to Cite?
AbstractNasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC 50 ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G 0/G 1 cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities. © 2010 Springer Science+Business Media, LLC.
Persistent Identifierhttp://hdl.handle.net/10722/137202
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID
Funding AgencyGrant Number
GlaxoSmithKline, UK
Funding Information:

This work was supported by a research grant from GlaxoSmithKline, UK (to T. Mok).

 

DC FieldValueLanguage
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorLau, CPYen_HK
dc.contributor.authorHo, Ken_HK
dc.contributor.authorNg, MHLen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorTsang, CMen_HK
dc.contributor.authorLei, KIKen_HK
dc.contributor.authorChan, ATen_HK
dc.contributor.authorMok, TSKen_HK
dc.date.accessioned2011-08-26T14:18:45Z-
dc.date.available2011-08-26T14:18:45Z-
dc.date.issued2010en_HK
dc.identifier.citationInvestigational New Drugs, 2010, p. 1-12en_HK
dc.identifier.issn0167-6997en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137202-
dc.description.abstractNasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC 50 ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G 0/G 1 cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities. © 2010 Springer Science+Business Media, LLC.en_HK
dc.languageengen_US
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.subjectAnoikis-sensitizationen_HK
dc.subjectAnti-invasionen_HK
dc.subjectLapatiniben_HK
dc.subjectNPCen_HK
dc.subject.meshAntineoplastic Agents - pharmacology-
dc.subject.meshCell Cycle - drug effects-
dc.subject.meshNasopharyngeal Neoplasms - drug therapy - pathology-
dc.subject.meshProtein Kinase Inhibitors - pharmacology-
dc.subject.meshQuinazolines - pharmacology-
dc.titleAnti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cellsen_HK
dc.typeArticleen_HK
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/s10637-010-9470-yen_HK
dc.identifier.pmid20571878-
dc.identifier.scopuseid_2-s2.0-84855522943-
dc.identifier.hkuros191856en_US
dc.identifier.volume29-
dc.identifier.issue6-
dc.identifier.spage1en_HK
dc.identifier.epage12en_HK
dc.identifier.isiWOS:000294824200013-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridLau, CPY=36608195100en_HK
dc.identifier.scopusauthoridHo, K=34971221500en_HK
dc.identifier.scopusauthoridNg, MHL=35292609300en_HK
dc.identifier.scopusauthoridCheng, SH=7404681588en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridTsang, CM=24831236400en_HK
dc.identifier.scopusauthoridLei, KIK=7102208067en_HK
dc.identifier.scopusauthoridChan, AT=13404833700en_HK
dc.identifier.scopusauthoridMok, TSK=7006561460en_HK
dc.identifier.citeulike7459386-

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