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Article: The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines

TitleThe activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines
Authors
KeywordsAKT
mTOR
Nasopharyngeal carcinoma
RAD001 (everolimus)
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, v. 28 n. 4, p. 413-420 How to Cite?
AbstractPhosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC50=0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pip70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation. © Springer Science + Business Media, LLC 2009.
Persistent Identifierhttp://hdl.handle.net/10722/124476
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID
Funding AgencyGrant Number
Li Ka Shing Institute for the Health Science, Chinese University of Hong Kong
Funding Information:

This study was supported in part by Li Ka Shing Institute for the Health Science, Chinese University of Hong Kong. Reprint requests should be sent to the corresponding author. The authors declare no conflict of interest with this manuscript. Result of this study was presented in part at the Annual Meeting of the American Association of Cancer Research, San Diego, CA, 2008. We thank Dr S. Hardikar and Novartis Pharmaceuticals Corporation for providing RAD001 in this study.

References

 

DC FieldValueLanguage
dc.contributor.authorMa, BBYen_HK
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorHui, EPen_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.authorChan, ATCen_HK
dc.date.accessioned2010-10-31T10:36:33Z-
dc.date.available2010-10-31T10:36:33Z-
dc.date.issued2010en_HK
dc.identifier.citationInvestigational New Drugs, 2010, v. 28 n. 4, p. 413-420en_HK
dc.identifier.issn0167-6997en_HK
dc.identifier.urihttp://hdl.handle.net/10722/124476-
dc.description.abstractPhosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC50=0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pip70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation. © Springer Science + Business Media, LLC 2009.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.subjectAKTen_HK
dc.subjectmTORen_HK
dc.subjectNasopharyngeal carcinomaen_HK
dc.subjectRAD001 (everolimus)en_HK
dc.titleThe activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell linesen_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/s10637-009-9269-xen_HK
dc.identifier.pmid19471857-
dc.identifier.scopuseid_2-s2.0-77956620903en_HK
dc.identifier.hkuros182814en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77956620903&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume28en_HK
dc.identifier.issue4en_HK
dc.identifier.spage413en_HK
dc.identifier.epage420en_HK
dc.identifier.isiWOS:000277942700005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridMa, BBY=7403301016en_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridHui, EP=7005081895en_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.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.citeulike4691549-

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