IGF-1R抑制剂联用可增强人非小细胞肺癌PC9/G细胞对吉非替尼的敏感性  

A combination with IGF-1R inhibitior enhances the sensitivity of human non-small cell lung cancer cell line PC9/G to gefitinib

作　　者：范理宏[1,2] 祁慧薇[2] 王杰军[1] 

机构地区：[1]第二军医大学长征医院肿瘤科,上海200070 [2]上海交通大学附属第六人民医院肺内科,上海200233

出　　处：《肿瘤》2011年第3期222-227,共6页Tumor

基　　金：上海市卫生局科研课题计划项目(编号:054014)

摘　　要：目的:观察单用表皮生长因子受体(epidermal growth factor receptor, EGFR)的酪氨酸激酶抑制剂吉非替尼 (ge? tinib) 或联合胰岛素生长因子-1受体(insulin-like growth factor-1 receptor,IGF-1R)的酪氨酸激酶抑制剂AG1024作用于人非小细胞肺癌耐药株PC9/G细胞后,该细胞对吉非替尼耐药性的影响,并探讨IGF-1R与肿瘤细胞耐药的相关机制。方法:用吉非替尼和AG1024单独或联合作用于PC9/G细胞后,采用MTT法分别检测各组细胞的增殖情况,并利用中效原理判断两药联用的效果;FCM法检测各组细胞的凋亡情况;Western印迹法检测各组细胞的磷酸化EGFR(phosphorylated EGFR, p-EGFR)、磷酸化Akt(phosphorylated Akt,p-Akt)和磷酸化细胞外信号调节激酶(phosphorylated extracellular signal-regulated kinase,p-ERK)的表达水平。结果:吉非替尼和AG1024单独作用于PC9/G细胞后,均出现不同程度的细胞增殖抑制作用和细胞凋亡促进作用;而吉非替尼和AG1024联合作用,能更显著地抑制细胞增殖,且凋亡细胞显著增加(P<0.05)。 Western印迹法检测发现,联合用药组的p-EGFR、p-Akt和p-ERK蛋白表达量明显减少。结论:IGF-1R抑制剂AG1024和EGFR抑制剂吉非替尼联用具有较好的协同作用,可能通过抑制细胞增殖和促进细胞凋亡,提高耐药细胞对吉非替尼的敏感性。Objective：To observe the effect of gefitinib alone or in combination with AG1024（a tyrosine kinase inhibitor of insulin-like growth factor-1 receptor） on drug resistance of human non-small cell lung cancer cell line PC9/G with acquired-resistance to gefitinib,and to discuss its possible mechanism.Methods：PC9/G cells were treated with AG1024 or gefitinib alone or in combination,the proliferative activity of PC9/G cells was detected by MTT method,and the efficacy of combination therapy was assessed by median-effects principle.Apoptosis rate of PC9/G cells was examined by flow cytometry.The expression levels of phosphorylated epidermal growth factor receptor（p-EGFR）,phosphorylated-Akt（p-Akt） and the phosphorylated extracellular signal-regulated kinase（p-ERK） in PC9/G cells were detected by Western blotting.Results：PC9/G cells displayed apoptotic features after treatment with AG1024 or gefitinib alone,and the cell proliferation was inhibited to different degrees.The treatment of AG1024 combined with gefitinib had a synergistic effect on the apoptosis and the cell proliferation（P0.05） of PC9/G cells,as well as the expression levels of p-EGFR,p-Akt and p-ERK proteins were decreased.Conclusion：AG1024 in combination with gefitinib exerts a synergistic effect,which may lead to the proliferation inhibition and the apoptosis enhancement,and eventually increases the sensitivity of human non-small cell lung cancer cell line PC9/G to gefitinib.

关 键 词：癌 非小细胞肺 受体 IGF1型 受体 表皮生长因子 蛋白激酶抑制药 抗药性 肿瘤 吉非替尼 

分 类 号：R734.2[医药卫生—肿瘤]