Objective Our purpose is to investigate the inhibitory effect and mechanism of a novel rapamycin containing triazole derivative FIM-X13 on gastric carcinoma as compared with rapamycin or everolimus separately. Methods The proliferation of cancer cells was tested by sulforhodamine B assay. The apoptosis and cell cycle of cancer cells were individually analyzed by flow cytometry. The expressions of mTOR, p70S6K1, S6, 4EBP1 and their phosphorylation level were separately detected by Western blot. Results FIM-X13 inhibited the proliferation of gastric carcinoma AGS cells in a dose-dependent manner with IC50 value of (9.32 ± 0.70) μmol/L and the inhibitory effect was even more potent than that of rapamycin and everolimus. It also induced apoptosis and G1 phase cell cycle arrested in AGS cells. In addition, FIM-X13 suppressed the phosphorylation level of mTOR and its downstream targets of 4EBP1, p70S6K1 and S6, which was consistent with rapamycin and everolimus. Conclusion The novel triazole-containing rapamycin derivate FIM-X13 exerts more potent effect on cell proliferation than rapamycin and everolimus do. Similar to rapamycin and everolimus, FIM-X13 significantly inhibits proliferation of gastric cancer cell, induces cell apoptosis and G1 phase cell cycle arrest via blocking mTOR pathway. FIM-X13 may become a promising mTOR inhibitor candidate for the treatment gastric carcinoma.%目的：研究雷帕霉素的三氮唑新衍生物 FIM-X13对人胃癌细胞株 AGS的作用，探讨其作用机制并分别与雷帕霉素和依维莫司比较。方法磺酰罗丹明 B检测 FIM-X13对 AGS增殖的抑制活性；流式细胞术检测 FIM-X13对 AGS细胞凋亡及周期影响；Western blot分析 AGS细胞内 mTOR、p70S6K1、S6和4EBP1的磷酸化水平。结果 FIM-X13能显著抑制 AGS细胞的增殖，IC50为（9.32±0.70）μmol/L，抑制能力强于雷帕霉素和依维莫司；FIM-X13能显著诱导 AGS细胞凋亡及阻滞细胞周期于 G1期，其诱导 AGS细胞凋亡和阻滞细胞周期的能力均强于雷帕霉素及依维莫司；FIM-X13能显著抑制 AGS细胞内 mTOR、p70S6K1、S6和4EBP1的磷酸化，抑制能力与雷帕霉素和依维莫司相当。结论雷帕霉素的三氮唑新衍生物 FIM-X13对人胃癌细胞株 AGS的抑制活性强于雷帕霉素和依维莫司。与雷帕霉素和依维莫司一样，FIM-X13主要通过抑制 AGS的 mTOR信号通路抑制细胞增殖、诱导细胞凋亡及阻滞细胞周期于 G1期等发挥抗肿瘤作用。
展开▼
