摘要
目的探讨通过联合应用磷脂酰肌醇3激酶(PI3K)/蛋白酶B(AKT)通路抑制剂BEZ235和细胞外调解蛋白激酶(ERK)通路抑制剂U0126抑制膜受体酪氨酸激酶/PI3K/AKT/雷帕霉素靶蛋白(mTOR)通路与ERK/丝裂原活化蛋白激酶通路对细胞增殖的影响。方法以磷酸酶和张力蛋白同源物缺失(PTEN-/-)的小鼠胚胎成纤维细胞(MEF)系作为研究对象,联合应用PI3K、mTOR双重抑制剂BEZ235及ERK激酶抑制剂U0126,通过MTT和Western blot方法检测药物对细胞增殖的影响。结果 BEZ235及U0126对PTEN-/-MEF细胞均有抑制作用,二者半数抑制浓度分别为6.257 nmol/L及22.85μmol/L。但联合应用BEZ235与U0126,二者表现为拮抗的作用方式。结论在PTEN缺失的细胞系中或PTEN突变的肿瘤的联合靶向治疗中,不推荐应用BEZ235与U0126联合使用。
Objective To study the inhibitory effect of the dual usage of BEZ235 and U0126, the in- hibitor of phosphatidyl inositol-3-kinase/protein kinase B pathway and extracellular regulated proteinkinase/mito- geM-activated protein kinase pathway, respectively, on cell proliferation. Methods Phosphatase and tensin homolog knockout mouse embryonic fibroblast (PTEN-/-MEF) cell lines were used as the cellular model for ma- lignant tumors. BEZ235, the dual inhibitor of phosphatidyl inositol-3-kinase and mammalian target of rapamycin, and U0126, the inhibitor of mitogen-activated protein kinase were used to treat the ceils individually and in a combination manner. The inhibitory effects to cell proliferation were monitored by MTT. Results Both BEZ235 and U0126 suppressed PTEN knockout cell proliferation, and their half inhibitory concentrations were 6. 257 nmol/L and 22.85 μmol/L, respectively. However, the combination treatment of the two drugs showed antago- nistic rather than synergistic effect on cell proliferation. Conclusion BEZ235 and U0126 are not suitable for a combined target therapy regimen.
出处
《中国医学科学院学报》
CAS
CSCD
北大核心
2013年第5期530-534,共5页
Acta Academiae Medicinae Sinicae
基金
国家自然科学基金(81101516)~~