蛋白激酶C抑制药enzastaurin对吉非替尼耐药的人非小细胞肺癌细胞株生长的影响  

Effect of Protein Kinase C Inhibitor Enzastaurin on Growth of Gefitinib-resistant Human Non-small Cell Lung Cancer Cell Lines

作　　者：沈云婕[1] 朱珺[1] 顾嘉钦[1] 沙慧芳[2] 

机构地区：[1]上海交通大学附属胸科医院药剂科,上海200030 [2]上海交通大学附属胸科医院胸部肿瘤研究所,上海200030

出　　处：《中国药师》2014年第4期529-533,共5页China Pharmacist

摘　　要：目的：观察新型靶向制剂enzastaurin单独或联合吉非替尼对耐药人非小细胞肺癌细胞株的影响,设计合理的治疗药物组合。方法：CCK8法检测细胞增殖,Chou-Talalay联用指数法判定联合用药效果,流式细胞仪检测细胞周期变化。结果：单药吉非替尼及enzastaurin作用NCI-H460耐药肺癌细胞72 h的半数抑制浓度（IC50）分别为6.99μmol·L-1（95%CI 3.55~13.79μmol·L-1）,7.25μmol·L-1（95%CI 4.77~1.02μmol·L-1）。两药联合应用对肺癌细胞的抑制作用增强（P 〈0.05）,同时给药组抑制效果更显著（P〈0.01）。同时给药组、序贯给药组（先用吉非替尼）和序贯给药组（先用enzastaurin）吉非替尼对H460细胞的IC50值分别为0.006μmol·L-1（95%CI 0.002~0.020μmol·L-1）,0.02μmol·L-1（95%CI 0.011~0.037μmol·L-1）,0.085μmol·L-1（95%CI 0.042~0.170μmol·L-1）。联合指数法显示在吉非替尼浓度0.05μmol·L-1以上时,同时给药组联合指数均〈1。细胞周期分布实验结果显示同时给药组可显著提高G0/G1期细胞比例（P〈0.05）,阻滞细胞于G1期。结论：蛋白激酶C抑制药enzastaurin与EGFR抑制药吉非替尼联用具有较好的协同作用,两药联合应用可能是出现吉非替尼耐药的非小细胞肺癌后续治疗的一个新选择。Objective： To observe the effect of a novel targeted agent enzastaurin alone or in combination with gefitinib on ge-fitinib-resistant human non-small cell lung cancer cells to explore the rational drug combination. Methods： CCK-8 assay was used to measure the cell proliferation. Combination index （ CI） was calculated by Chou-Talalay method to assess the efficacy of the combination therapy. The flow cytometry （FCM） was used to analyze the change in the cell cycle. Results：In 72h, the IC50 value of gefitinib and enzastaurin for the lung cancer NCI-H460 cells was 6. 99μmol·L-1 （95%CI：3. 55-13. 79μmol·L-1 ） and 7. 25μmol·L-1 （95%CI：4. 77-1. 02 μmol·L-1）, respectively. The inhibition effect on the cell proliferation was stronger in the combination treatment than that in the monotherapy （P〈0. 05）, and the simultaneous treatment showed the most significant inhibition effect （P〈0. 01）. The IC50 value of gefitinib for H460 cells in the simultaneous administration group, the sequential administration group with gefitinib used first and the sequential administration group with enzastaurin used first was 0.006 μmol·L-1（95%CI：0.002-0.020μmol·L-1）, 0.02μmol·L-1（95%CI：0.011-0.037 μmol·L-1） and 0.085 μmol·L-1（95% CI：0.042-0.170μmol·L-1, respectively. The CI of the simultaneous administration group was lower than one when the gefitinib concentration was above 0. 05μmol·L-1 . The cell cycle distribution result indicated that the simultaneous administration group had significantly increased G0/G1 proportion （P〈0. 05） and induced cell cycle arrest at G1 phase. Conclusion：Protein kinase C inhibitor enzastaurin combined with EGFR inhibitor gefitinib shows a synergistic effect, suggesting that the combination treatment of the two drugs might be a new strategy for the follow-up therapy of gefitinib-resistant non-small cell lung cancer.

关 键 词：非小细胞肺癌 吉非替尼 耐药性 蛋白激酶C抑制药 ENZASTAURIN 

分 类 号：R965.1[医药卫生—药理学]