PI3K/Akt抑制剂联合西妥昔单抗对人肺癌细胞的体外抑制作用(1)
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[摘要] 目的 探讨PI3K/Akt抑制剂LY294002单独或联合西妥昔单抗对人肺癌细胞株A549的作用，以期为肺癌临床治疗方案的选择、用药顺序提供新的理论依据。 方法 选用西妥昔单抗和LY294002，分析单药及不同浓度和联合作用方式对A549细胞增殖的影响；计算IC50值和CI值，分析药物联合作用的效应是协同、相加抑或拮抗。 结果 单独作用时，西妥昔单抗与LY294002最大抑制率分别为(57.3±6.2)%、(56.2±6.0)%；联合作用时，LY294002→西妥昔单抗序贯给药(CI = 0.41)比同步应用(CI = 0.73)可增强疗效，其最大抑制率分别为(84.9±7.5)%和(79.0±7.3)%。 结论两药对A549细胞增殖均具有抑制作用，LY294002→西妥昔单抗序贯联合应用对A549细胞的增殖抑制率最高。
[关键词] 肺癌细胞株；磷脂酰肌醇—3—激酶/丝苏氨酸蛋白激酶；LY294002；西妥昔单抗
[中图分类号] R734.2 [文献标识码] A [文章编号] 1673—9701(2012)27—0006—03
Effects of cetuximab combined inhibitor of PI3K/Akt on proliferation of human lung carcinoma cell lines A549
SHEN Hui
Department of Respiratory Medicine，Huzhou Central Hospital in Zhejiang Province，Huzhou 313000，China
[Abstract] Objective To evaluate the effects of cetuximab and inhibitor of phosphatidylinositol 3—kinase/Akt(PI3K/Akt) LY294002 on proliferation of non—small cell lung cancer (NSCLC) lines A549 alone and in different sequences of combinations. Methods Cetuximaband LY294002， alone or in combination were administrated to A549 cells with different sequences. The IC50 and the combination index(CI) of these two agents were calculated. Results The single agent of cetuximab and LY294002 inhibited the proliferation of A549 cells in a dose—dependent manner. The proliferation inhibition rates of A549 cells were (57.3±6.2)% and (56.2±6.0)%. When cetuximab was combined with LY294002 synchronously，the maximal inhibitory effect of the proliferation inhibition rate of A549 was (79.0±7.3)%. At that time，the CI of the two agents at IC50 points was 0.73，suggested that they had obvious synergistic activity. While，when LY294002 was followed by cetuximab，the maximal inhibitory effect of the proliferation inhibition rate of A549 was (84.9±7.5)% and the CI of the two agents at IC50 points was 0.41. Conclusion The single agent of cetuximab and LY294002 can inhibit the proliferation of A549 cells，and they have obvious synergistic activity. The optimal treatment sequence is LY294002 followed by cetuximab，and it can obtain obvious synergistic activity and conduce to less doses in clinical application.
[Key words] Lung cancer cell lines； PI3K/Akt； LY294002； Cetuximab
肺癌是当今世界上严重威胁人类健康与生命的恶性肿瘤，发病率在多数国家呈明显上升趋势，全球每年有超过100万人死于肺癌，其中约85%死于非小细胞肺癌(non—small cell lung cancer，NSCLC)[1]。世界卫生组织报告肺癌和艾滋病将是21世纪危害人类健康最严重的疾病。目前针对NSCLC的治疗方法主要包括手术、放疗、化疗等。化疗虽然能改善NSCLC患者的生存率，然而5年存活率仅为15%[2]。因此，进一步研究肺癌的发生、发展以及转移的分子机制，寻找针对肺癌的靶向治疗手段是非常必要的。近年有关磷脂酰肌醇—3—激酶/丝苏氨酸蛋白激酶(PI3K/Akt)信号转导通路在控制基因表达、细胞增殖和凋亡等生理功能方面的研究引起了人们的重视。Akt的过度激活与肿瘤的发生、发展及侵袭、转移有关，并且大多数NSCLC患者的Akt表达明显升高，说明PI3K/Akt信号通路对于NSCLC的发生发展有重要的影响[3，4]。PI3K/Akt抑制剂LY294002 [2—(4—吗啉基)—8—苯基—4氢—1—苯并吡喃—4—酮]可增强某些抗肿瘤药物的疗效，减少化疗抵抗[5，6]。但是，LY294002对肺癌的研究尚不多见，尤其是LY294002与西妥昔单抗(Cetuximab，C—225)联合应用对人肺癌细胞增殖的抑制作用是否存在协同作用及不同联合作用方式对抑制作用的影响等研究目前仍无文献报道。
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