雷帕霉素三氮唑新衍生物FIM-X13对人胃癌细胞株MGC80-3的作用

Effect of a Novel Rapamycin Derivative Containing Triazole FIM-X13 on Human Gastric Cancer Cell Line MGC80-3

目的研究雷帕霉素三氮唑新衍生物FIM-X13对人胃癌细胞株MGC80-3的作用,探讨其作为mTOR靶向抗胃癌药物的潜力。方法用磺酰罗丹明B检测细胞增殖;流式细胞仪检测细胞凋亡和细胞周期的影响;Western blot分析细胞内mTOR、p70S6K1、S6和4EBP1的磷酸化水平。结果 FIM-X13显著地抑制MGC80-3细胞的增殖,IC_(50)为14.73±0.64μmol·L^(-1);FIM-X13诱导MGC80-3细胞凋亡;阻滞细胞周期于G_1期;FIM-X13能显著抑制MGC80-3细胞内mTOR、p70S6K1和S6激酶的磷酸化。结论雷帕霉素的三氮唑新衍生物FIM-X13对人胃癌细胞株MGC80-3的抑制活性强于雷帕霉素和依维莫司,可以作为mTOR靶向抗胃癌药物开展进一步研究。

OBJECTIVE To study the effect of a novel rapamycin derivative containing triazole FIM-X13 on human gastric cancer cell line MGC80-3,and explore its potential as an anti gastric cancer drug targeting mTOR. METHODS Cell proliferation inhibition was evaluated by sulforhodamine B assay,apoptosis and cell cycle analyses were performed by flow cytometry,expression and phosphorylation of mTOR,4EBP1,p70S6K1 and S6 were analyzed by SDS-polyacrylamide gel electrophoresis,following Western blotting RESULTS FIM-X13 inhibited gastric carcinoma MGC80-3 cell proliferation in a dose-dependent manner with IC 50 value of 14.73±0.64μmol·L -1 ,which was stronger than that of rapamycin and everolimus.It also dose-dependently induced MGC80-3 cells apoptosis and G 1 phase cell cycle arrest.In addition,FIM-X13 inhibited the phosphorylation of mTOR and its downstream kinases p70S6K1,S6 and 4EBP1,and inhibition effect on the phosphorylation of 4EBP1 was more potent than that of rapamycin and everolimus. CONCLUSION The novel rapamycin containing triazole derivate FIM-X13 showed stronger inhibition effect on MGC80-3 than that of rapamycin and everolimus,it may have the potential to become a new mTOR inhibitor against gastric cancer.