Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines
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摘要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 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.
著者Ma BBY, Lui VWY, Cheung CS, Lau CPY, Ho K, Hui EP, Tsui SKW, Ng MH, Cheng SH, Ng PKS, Tsao SW, Chan ATC
期刊名稱Investigational New Drugs
詳細描述Epub ahead of print.
出版年份2013
月份2
日期1
卷號31
期次1
出版社SPRINGER
頁次30 - 38
國際標準期刊號0167-6997
電子國際標準期刊號1573-0646
語言英式英語
關鍵詞BRAF mutation; Gefitinib; MEK; Nasopharyngeal cancer; Selumetinib
Web of Science 學科類別Oncology; ONCOLOGY; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

上次更新時間 2021-25-02 於 01:32