Celecoxib Enhanced the Sensitivity of Cancer Cells to Anticancer Drugs by Inhibition of the Expression of P-Glycoprotein Through a COX-2-Independent Manner
Celecoxib Enhanced the Sensitivity of Cancer Cells to Anticancer Drugs by Inhibition of the Expression of P-Glycoprotein Through a COX-2-Independent Manner
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塞来昔布通过不依赖COX-2的方式抑制P-糖蛋白的表达，增强癌细胞对抗癌药物的敏感性
DOI：
10.1002/jcb.22239
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发表时间：
2009-09-01
影响因子：
4
通讯作者：
Sun, Yujie
中科院分区：
文献类型：
--
作者：
Xia, Wenhong;Zhao, Tao;Sun, Yujie
人MDR 1基因编码的P-糖蛋白（p170，P-gp）具有泵的功能，将抗癌药物从癌细胞中排出。p 170过表达与肿瘤细胞的原发性和诱导性耐药表型密切相关。最近的研究表明，环氧合酶-2（考克斯-2）的表达与p170水平呈正相关，提示考克斯-2特异性抑制剂可能在调节抗癌药物的细胞毒性中发挥作用。塞来昔布是考克斯-2的特异性抑制剂之一，已广泛应用于临床。然而，其在肿瘤细胞对抗癌药物应答中的作用及其相关机制仍有待进一步研究。为探讨塞来昔布与p170介导的耐药的相关性，采用流式细胞仪、高效液相色谱（HPLC）和集落形成实验分析塞来昔布在肿瘤细胞耐药中的作用。塞来昔布（50 μ M）通过抑制p170表达和增加药物的细胞内积累，分别显著增强MCF-7和MCF/VP 16细胞对他莫昔芬和依托泊苷的敏感性。但是，塞来昔布并不影响p170的泵功能。酶活性和甲基化分析表明，塞来昔布对p170的抑制作用不依赖于考克斯-2，而与MDR 1基因启动子的高甲基化密切相关。我们的研究表明，塞来昔布是一种潜在的药物，以增加癌细胞的敏感性抗癌药物。这也提供了MDR 1的表观遗传变化与癌细胞的药物反应之间的联系。J.细胞。108：181-194，2009. (C)2009 Wiley-Liss，Inc.
The P-glycoprotein (p 170, P-gp) encoded by human MDR1 gene functions as a Pump to extrude anticancer drugs from cancer cells. Overexpression of p 170 is closely related to primary and induced drug resistance phenotype of tumor cells. Recent studies have demonstrated that expression of cyclooxygenase-2 (COX-2) is positively correlated with the p 170 level, suggesting a potential of COX-2 specific inhibitors in regulation of cytotoxicity of anticancer agents. Celecoxib is one of the specific inhibitors of COX-2 and has been widely used in clinic. However, its function in the response of cancer cells to anticancer drugs and the related mechanism are still waiting to be investigated. To explore the correlation of celecoxib and the p170-mediated drug resistance, the role of celecoxib in drug response of cancer cells was analyzed with flow cytometry, high performance liquid chromatography (HPLC), and colony formation experiments. Celecoxib (50 mu M) was found to significantly enhance the sensitivity of MCF-7 and JAR/VP16 cells to tamoxifen and etoposide, respectively, by inhibition of p 170 expression and increase in intracellular accumulation of the drugs. However, celecoxib did not affect pump function of p170. Enzyme activity and methylation analyses demonstrated that the inhibitory effect of celecoxib on p170 was independent on COX-2 but closely related to hypermethylation of MDR1 gene promoter. Our study suggested that celecoxib was a potential agent for enhancement of the sensitivity of cancer cells to anticancer drugs. It also provided a links between epigenetic change of MDR1 and drug response of cancer cells. J. Cell. Biochem. 108: 181-194, 2009. (C) 2009 Wiley-Liss, Inc.