雷帕霉素的三氮唑新衍生物FIM-X13对人胃癌细胞株AGS的作用及机制的初步研究  

Preliminary study on effect and mechanism of a novel rapamycin containing triazole derivative FIM-X13 on gastric carcinoma AGS cell line

作　　者：杨丹[1,2] 陈晓明[2] 李夸良[2] 谢立君[2] 潘福生 黄捷[1,2] 

机构地区：[1]福建中医药大学药学院,福州350122 [2]福建省微生物研究所,福州350007 [3]杭州华东医药集团新药研究院有限公司,310012

出　　处：《中国医药生物技术》2016年第3期224-228,共5页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81502935);福建省属工艺类科研院所基本科研专项(2015R1009-7)

摘　　要：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m TOR、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,IC_(50)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G_1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m TOR、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m TOR信号通路抑制细胞增殖、诱导细胞凋亡及阻滞细胞周期于G_1期等发挥抗肿瘤作用。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 m TOR, 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 IC_（50） 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 G_1 phase cell cycle arrested in AGS cells. In addition, FIM-X13 suppressed the phosphorylation level of m TOR 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 G_1 phase cell cycle arrest via blocking m TOR pathway. FIM-X13 may become a promising m TOR inhibitor candidate for the treatment gastric carcinoma.

关 键 词：胃肿瘤 哺乳动物雷帕霉素靶蛋白 雷帕霉素三氮唑衍生物 

分 类 号：R735.2[医药卫生—肿瘤]