吲哚美辛与埃罗替尼对胰腺癌细胞生长的协同抑制作用  

Synergistic Inhibitory Effect of Indomethacin and Erlotinib on the Growth of Pancreatic Cancer Cells

作　　者：陆颖影[1] 靖大道[1] 王兴鹏[1] 吴恺[1] 

机构地区：[1]上海交通大学附属第一人民医院消化内科,200080

出　　处：《胃肠病学》2007年第4期209-213,共5页Chinese Journal of Gastroenterology

摘　　要：背景:目前胰腺癌药物化疗疗效不佳。既往研究提示环氧合酶(COX)-2和表皮生长因子受体(EGFR)信号途径均参与了胰腺癌的发生、发展,COX-2抑制剂和EGFR抑制剂联用对胰腺癌的生长可能具有协同抑制作用。目的:观察COX-2抑制剂吲哚美辛与EGFR酪氨酸激酶抑制剂埃罗替尼对胰腺癌细胞生长的协同抑制作用。方法:以甲基噻唑基四唑(MTT)比色法检测胰腺癌细胞株BxPC-3的增殖情况,以流式细胞分析和原位末端标记(TUNEL)法观察用药前后细胞凋亡和细胞周期的变化,以逆转录聚合酶链反应(RT-PCR)观察用药前后细胞中COX-2、EGFR以及凋亡相关基因Bcl-2、Bax、Bcl-xL、BakmRNA表达的变化。结果:BxPC-3细胞中可观察到COX-2和EGFRmRNA表达,吲哚美辛和埃罗替尼单用均可下调COX-2和EGFRmRNA的表达,两者联用时下调作用更明显。吲哚美辛和埃罗替尼单用均可抑制BxPC-3细胞增殖,促进细胞凋亡,诱导细胞周期阻滞于G0/G1期,减少抗凋亡基因Bcl-2、Bcl-xL的表达,轻微上调促凋亡基因Bax的表达,两者联用对细胞生长的抑制作用增强。结论:吲哚美辛和埃罗替尼均可抑制COX-2和EGFR的表达,下调Bcl-2/Bax比值,两者联用对胰腺癌细胞生长具有协同抑制作用。Background： The efficacy of chemotherapy in pancreatic cancer is still poor. Previous studies had shown that cyclooxygenase （COX）-2 and epidermal growth factor receptor （EGFR） signal pathways were involved in the development and progress of pancreatic cancer. Hence, the combined use of COX-2 inhibitor and EGFR blocker may have synergistic inhibitory effect on the growth of pancreatic cancer. Aims： To investigate the synergistic inhibitory effect of COX-2 inhibitor （indomethacin） and EGFR blocker （edotinib） on the growth of pancreatic cancer cells. Methods： The effects of indomethacin, erlotinib and their combination on the cell growth, apoptosis and cell cycle in pancreatic cancer cell line BxPC-3 were studied by methyl thiazolyl tetrazolium （MTT） assay, flow cytometry and terminal TdT-mediated dUTP-biotin nick-end labeling （TUNEL）. Reverse transcriptase polymerase chain reaction （RT-PCR） was used to evaluate the expression of COX-2 and EGFR mRNA and to detect the mRNA expression of apoptosis-associated genes such as Bcl-2, Bax, Bcl-xL and Bak. Results： Expression of COX-2 and EGFR mRNA was detected in BxPC-3 cells, treatment with indomethacin or erlotinib could down-regulate the expression of COX-2 and EGFR mRNA, and combined use of the two resulted in a synergistic effect. Growth inhibition, apoptosis and cell cycle G0/G1 arrest were significantly higher in BxPC- 3 cells treated with indomethacin combined with edotinib than those in cells treated with either alone. Indomethacin and edotinib down-regulated the expression of anti-apoptotic gene Bcl-2 and Bcl-xL, and mildly up-regulated the expression of pro-apoptotic gene Bax. Their combined use had a synergistic inhibitory effect on the growth of BxPC-3 cells. Conclusions： Indomethacin and edotinib can reduce both the expression of COX-2 and EGFR, down-regulate the Bcl-2/ Bax ratio. Their combined use has synergistic inhibitory effect on the growth of pancreatic cancer cells.

关 键 词：胰腺肿瘤 环氧化酶2抑制剂 受体 表皮生长因子/拮抗剂和抑制剂 凋亡 

分 类 号：R735.9[医药卫生—肿瘤]