Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study
Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study
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DOI：
10.1007/s12032-007-9015-1
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发表时间：
2008-06-01
期刊：
影响因子：
3.4
通讯作者：
Wei, Weidong
中科院分区：
文献类型：
--
作者：
Chen, Likun;He, Youjian;Wei, Weidong
非小细胞肺癌（NSCLC）中经常出现环氧合酶-2（考克斯-2）和表皮生长因子受体（EGFR）的组成性表达。近年来以EGFR为靶点的抗癌研究受到广泛关注，尤其是在NSCLC中，考克斯-2抑制剂也显示出一定的抗癌活性。同时靶向考克斯-2和EGFR可能是一种有前景的治疗方法。本研究采用选择性考克斯-2抑制剂塞来昔布联合表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）ZD 1839对非小细胞肺癌细胞株进行体外抗增殖作用研究，并探讨其细胞分子机制。MTT法显示一定浓度的塞来昔布与ZD 1839联合应用具有协同治疗作用，Hoechest 33258荧光染色和流式细胞仪检测联合应用对细胞凋亡的影响。在蛋白质印迹分析中，ZD 1839单药抑制EGFR和下游细胞信号转导AKT和细胞外信号调节激酶（ERK）通路的活化、核因子-κ B（NF-κ B）的转录活性和考克斯-2的表达。塞来昔布单药对AKT和ERK通路也有抑制作用，甚至在高浓度时对EGFR表达也有抑制作用。塞来昔布联合ZD 1839对NSCLC相关细胞信号转导通路的抑制作用更强。
Constitutive expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) occurs frequently in non-small cell lung cancer (NSCLC). Anticancer research targeting EGFR has got an extensive attention especially in NSCLC and COX-2 inhibitor also shown a certain anticancer activity in recent years. Simultaneously targeting COX-2 and EGFR may be a promising therapeutic way. We carried out the in vitro study using selective COX-2 inhibitor celecoxib combined with EGFR-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 on NSCLC cell lines to investigate the anti proliferation effect and the cell molecular mechanism. MTT growth assay showed the synergistic therapeutic effect of certain concentration of celecoxib combined with ZD1839 and synergistic apoptosis effect was detected by Hoechest33258 fluorescence staining and flow cytometric analysis. In western blot analysis, ZD1839 single agent inhibited the activation of EGFR and downstream cell signal transduction AKT and extrocellular signal-regulated kinase (ERK) pathways, the transcription activity of nuclear factor-kappa B (NF-kappa B), and the expression of COX-2. Celecoxib single agent could also inhibit AKT and ERK pathway in NSCLC, even the EGFR expression under high concentration treatment. Celecoxib combined with ZD1839 led to stronger inhibition of related cell signal transduction pathways in NSCLC.