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目的观察丝裂原激活蛋白激酶的激酶(MEK)抑制剂CQN系列化合物对A549细胞体外抗肿瘤作用。方法采用非小细胞肺癌A549细胞(K-ras突变)体外抗肿瘤增殖抑制实验对9个CQN系列MEK抑制剂进行筛选,得到具有显著抗肿瘤活性的化合物。通过流式细胞术检测化合物对细胞周期和凋亡的影响;并通过ELISA法检测化合物对肿瘤发生关键蛋白ERK1/2磷酸化的抑制作用;通过细胞划痕实验检测化合物对细胞迁移能力的影响。结果细胞增殖实验筛选出高活性化合物CQN-4和CQN-5,两者的体外抗A549细胞增殖抑制活性与对照药曲美替尼(trametinib)相当。CQN-4和CQN-5可将A549细胞阻滞于G1期,与对照相比可使细胞凋亡率明显增加(P<0.01),且呈浓度依赖性。与对照相比,CQN-4和CQN-5对A549细胞ERK1/2磷酸化均有抑制作用(P<0.01),且具有浓度依赖性。细胞划痕愈合实验显示CQN-4和CQN-5对A549细胞迁移有显著的抑制作用,且具有浓度依赖性。结论 MEK抑制剂化合物CQN-4和CQN-5对A549细胞具有显著的体外抗肿瘤活性。
Objective To observe the anti-tumor effect of CQN compounds, a mitogen-activated protein kinase kinase (MEK) inhibitor, on A549 cells in vitro. Methods Nine CQN series MEK inhibitors were screened in vitro by anti-tumor proliferation inhibition of non-small cell lung cancer A549 cells (K-ras mutation), and the compounds with significant anti-tumor activity were obtained. The effect of the compound on cell cycle and apoptosis was detected by flow cytometry. The inhibitory effect of the compound on the phosphorylation of ERK1 / 2, a key protein of tumorigenesis, was detected by ELISA. The cell migration was evaluated by cell scratch assay. Results Highly active compounds CQN-4 and CQN-5 were screened out by cell proliferation assay. Both of them showed similar inhibitory activity against proliferation of A549 cells in comparison with the control drug trametinib. A549 cells were arrested in G1 phase by CQN-4 and CQN-5. Compared with the control, CQN-4 and CQN-5 could significantly increase the apoptosis rate (P <0.01) and in a concentration-dependent manner. Compared with the control, CQN-4 and CQN-5 inhibited the phosphorylation of ERK1 / 2 in A549 cells (P <0.01) in a concentration-dependent manner. Cell scratch healing experiments showed that CQN-4 and CQN-5 on A549 cell migration was significantly inhibited, and in a concentration-dependent manner. Conclusion The MEK inhibitor compounds CQN-4 and CQN-5 have significant antitumor activity against A549 cells in vitro.