Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines
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AbstractThis 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 mu M, HK1-LMP1(B95.8) = 0.17 mu M, HONE-1-EBV = 0.46 mu M, HONE-1 = 1.79 mu M, CNE-2 = 2.20 mu M and C666-1 > 10 mu M. 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 mu M and 5 mu M, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G(0)/G(1) 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 mu M) 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 mu M) 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.
All Author(s) ListMa BBY, Lui VWY, Cheung CS, Lau CPY, Ho K, Hui EP, Tsui SKW, Ng MH, Cheng SH, Ng PKS, Tsao SW, Chan ATC
Journal nameInvestigational New Drugs
Detailed descriptionEpub ahead of print.
Volume Number31
Issue Number1
Pages30 - 38
LanguagesEnglish-United Kingdom
KeywordsBRAF mutation; Gefitinib; MEK; Nasopharyngeal cancer; Selumetinib
Web of Science Subject CategoriesOncology; ONCOLOGY; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

Last updated on 2022-17-01 at 00:09