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Article: Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines

TitleActivity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines
Authors
Issue Date2013
Citation
Investigational New Drugs, 2013, v. 31 n. 1, p. 30-38 How to Cite?
AbstractSummary: This study evaluated the preclinical activity of selumetinib (AZD6244, ARRY-142866), an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK1/2) in 6 nasopharyngeal cancer (NPC) cell lines. Selumetinib could achieve up to 90 % inhibition of cell growth with the respective IC50 values in NPC cell lines as follow: HK1 = 0.04 μM, HK1-LMP1(B95.8) = 0.17 μM, HONE-1-EBV = 0.46 μM, HONE-1 = 1.79 μM, CNE-2 = 2.20 μM and C666-1 > 10 μM. The drug-sensitive cell lines HK1, HK1-LMP1(B95.8) and HONE-1-EBV have higher basal expression of phosphorylated (pi)-MAPK than the less sensitive cell lines. BRAF mutations were not detected in all 6 cell lines. Re-introduction of the EBV genome into HONE-1 cells, generating the HONE-1-EBV cell line, seemed to result in elevated expression of pi-MAPK and sensitivity to selumetinib when compared with the parental HONE-1 cells. At a concentration of 0.5 μM and 5 μM, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G0/G1 cycle arrest in HONE-1-EBV and HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC25 concentration) and the EGFR tyrosine kinase inhibitor, gefitinib (at concentrations of 0.1, 3 and 9 μM) resulted in synergistic growth inhibition in HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC25 concentration) and cisplatin (at concentrations of 0.1, 0.4, 0.8 and 2 μM) resulted in synergistic growth inhibition in HONE-1 and HONE-1-EBV cells. This result suggests that selumetinib alone or in combination with gefitinib or cisplatin maybe a promising strategy against NPC. Further studies are warranted. © 2012 Springer Science+Business Media, LLC.
Persistent Identifierhttp://hdl.handle.net/10722/194495
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, BBY-
dc.contributor.authorLui, VWY-
dc.contributor.authorCheung, CS-
dc.contributor.authorLau, CPY-
dc.contributor.authorHo, K-
dc.contributor.authorHui, EP-
dc.contributor.authorTsui, SKW-
dc.contributor.authorNg, MH-
dc.contributor.authorCheng, SH-
dc.contributor.authorNg, PKS-
dc.contributor.authorTsao, SW-
dc.contributor.authorChan, ATC-
dc.date.accessioned2014-01-30T03:32:39Z-
dc.date.available2014-01-30T03:32:39Z-
dc.date.issued2013-
dc.identifier.citationInvestigational New Drugs, 2013, v. 31 n. 1, p. 30-38-
dc.identifier.issn0167-6997-
dc.identifier.urihttp://hdl.handle.net/10722/194495-
dc.description.abstractSummary: This study evaluated the preclinical activity of selumetinib (AZD6244, ARRY-142866), an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK1/2) in 6 nasopharyngeal cancer (NPC) cell lines. Selumetinib could achieve up to 90 % inhibition of cell growth with the respective IC50 values in NPC cell lines as follow: HK1 = 0.04 μM, HK1-LMP1(B95.8) = 0.17 μM, HONE-1-EBV = 0.46 μM, HONE-1 = 1.79 μM, CNE-2 = 2.20 μM and C666-1 > 10 μM. The drug-sensitive cell lines HK1, HK1-LMP1(B95.8) and HONE-1-EBV have higher basal expression of phosphorylated (pi)-MAPK than the less sensitive cell lines. BRAF mutations were not detected in all 6 cell lines. Re-introduction of the EBV genome into HONE-1 cells, generating the HONE-1-EBV cell line, seemed to result in elevated expression of pi-MAPK and sensitivity to selumetinib when compared with the parental HONE-1 cells. At a concentration of 0.5 μM and 5 μM, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G0/G1 cycle arrest in HONE-1-EBV and HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC25 concentration) and the EGFR tyrosine kinase inhibitor, gefitinib (at concentrations of 0.1, 3 and 9 μM) resulted in synergistic growth inhibition in HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC25 concentration) and cisplatin (at concentrations of 0.1, 0.4, 0.8 and 2 μM) resulted in synergistic growth inhibition in HONE-1 and HONE-1-EBV cells. This result suggests that selumetinib alone or in combination with gefitinib or cisplatin maybe a promising strategy against NPC. Further studies are warranted. © 2012 Springer Science+Business Media, LLC.-
dc.languageeng-
dc.relation.ispartofInvestigational New Drugs-
dc.titleActivity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s10637-012-9828-4-
dc.identifier.pmid22565394-
dc.identifier.scopuseid_2-s2.0-84873097361-
dc.identifier.hkuros217733-
dc.identifier.volume31-
dc.identifier.issue1-
dc.identifier.spage30-
dc.identifier.epage38-
dc.identifier.isiWOS:000314029900004-

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