Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines
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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.
KeywordsSelumetinib Gefitinib Nasopharyngeal cancer MEK BRAF mutation
This work was funded by the Direct Grant for Research (Ref: 2006.2.015), The Chinese University of Hong Kong. Selumetinib was kindly provided by Astra Zeneca Ltd (UK) via the Cancer Therapy Evaluation Program, NCI, Bethesda, USA. VWYL is supported by research fund from the Pittsburgh Foundation, the Patricia L. Knebel Fund. This study was presented in part at the American Association of Cancer Research Special Symposium on ‘Infection and Cancer’ (abstract #C10), December 2008.
Conflict of interest statement
The authors declare that they have no conflict of interest.
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