安罗替尼联合吉非替尼对吉非替尼耐药非小细胞肺癌PC9/GR细胞增殖的影响及其可能的作用机制  

Effect of combining anlotinib with gefitinib on proliferation of non⁃small cell lung cancer PC9/GR cells and its possible mechanism

作　　者：吴敏[1] 金蒙蒙[1] 曹晓慧[1] 李永怀[1] WU Min;JIN Mengmeng;CAO Xiaohui;LI Yonghuai(Department of Respiratory and Critical Care Medicine,the First Affiliated Hospital of Anhui Medical University,Anhui Public Health Clinical Center,Hefei 230061,China)

机构地区：[1]安徽医科大学第一附属医院,安徽省公共卫生临床中心呼吸与危重症医学科,合肥230061

出　　处：《中国癌症防治杂志》2022年第5期503-508,共6页CHINESE JOURNAL OF ONCOLOGY PREVENTION AND TREATMENT

基　　金：安徽高校自然科学研究重点项目(KJ2019A0269);安徽省卫生健康委科研重点项目(AHWJ2021a014)。

摘　　要：目的探讨安罗替尼联合吉非替尼对吉非替尼耐药的人非小细胞肺癌PC9/GR(gefitinib resistance)细胞增殖的影响及其可能的作用机制。方法依据不同给药情况将PC9/GR细胞分为安罗替尼单药组、吉非替尼单药组、安罗替尼和吉非替尼联合用药组及阴性对照组,用MTT法检测各组细胞的增殖情况,流式细胞仪检测细胞的周期分布,Western blot检测p-ERK1/2和p-AKT蛋白的表达水平。结果安罗替尼和吉非替尼作用于PC9/GR细胞72 h的半数抑制浓度(half inhibitory concentration,IC_(50))分别为(1.91±0.18)μmol/L和(4.83±0.15)μmol/L,两药均呈剂量依赖性的抗增殖作用,且两药联合时表现出明显的协同效应,联合指数(combination index,CI)小于1。安罗替尼和吉非替尼单药均可将PC9/GR细胞阻滞于G0/G1期(均P<0.05)。与各单药组比较,联合用药组表现出更明显的G0/G1期阻滞(均P<0.05),且下调p-ERK1/2和p-AKT蛋白的表达水平(均P<0.05)。结论安罗替尼联合吉非替尼对非小细胞肺癌PC9/GR细胞具有协同抗增殖作用,且可增强吉非替尼敏感性,其协同抗肿瘤机制可能与诱导细胞周期阻滞和下调p-ERK1/2和p-AKT蛋白的表达相关。Objective To investigate the effect of combining anlotinib with gefitinib on the proliferation of gefitinib-resistant human non-small cell lung cancer(NSCLC)PC9/GR cells and its possible mechanism.Methods The PC9/GR cells were divided into anlotinib group,gefitinib group,anlotinib combined with gefitinib group and control group,respectively,according to different drug administrations.MTT assay was used to detect the cell proliferation.Flow cytometry was used to analyze the distribution of cell cycle.The protein expression levels of p-ERK1/2 and p-AKT were detected by Western blot.Results The half inhibitory concentrations(IC_(50))of anlotinib and gefitinib in PC9/GR cells for 72 h were(1.91±0.18)μmol/L and(4.83±0.15)μmol/L,respectively.Both drugs showed anti-proliferation effects of dose-dependent,and the combination of the two drugs showed obvious synergistic effects,with a combination index(CI)less than 1.The anlotinib and gefitinib could arrest PC9/GR cells at G0/G1 phase(all P<0.05).Compared with the single drug group,the G0/G1 phase arrest in the combination group wer more significant,significantly down-regulating the protein expression of p-ERK1/2 and p-AKT(all P<0.05).Conclusions The anlotinib combined with gefitinib has synergistic anti-proliferation effect on non-small cell lung cancer PC9/GR cells,and can improve the sensitivity of gefitinib.The synergistic anti-tumor mechanism may be related to the induction of cell cycle arrest and down-regulation of p-ERK1/2 and p-AKT protein expressions.

关 键 词：非小细胞肺癌 耐药 吉非替尼 安罗替尼 

分 类 号：R734.2[医药卫生—肿瘤]