新型AKT抑制剂Hu7691对胃癌细胞的抗肿瘤活性及机制研究  

Anti-cancer Efficacy Against Gastric Cancer Cells and Mechanism Study of a Novel AKT Inhibitor Hu7691

作　　者：郑琳[1,2] 代晓阳[1,2] 张燕 董晓武 翁勤洁[1,2] ZHENG Lin;DAI Xiaoyang;ZHANG Yan;DONG Xiaowu;WENG Qinjie(Zhejiang University,College of Pharmaceutical Sciences,Hangzhou 310058,China;Zhejiang University,Center for Drug Safety Evaluation and Research,Hangzhou 310058,China)

机构地区：[1]浙江大学药学院,杭州310058 [2]浙江大学药物安全评价研究中心,杭州310058

出　　处：《中国现代应用药学》2021年第16期1921-1927,共7页Chinese Journal of Modern Applied Pharmacy

基　　金：中国博士后科学基金面上项目(2020M671766)。

摘　　要：目的考察新型AKT抑制剂Hu7691对胃癌细胞的体内外抗肿瘤活性及作用机制。方法以人胃癌细胞HGC27和BGC823为体外细胞模型,采用SRB法评价不同浓度的Hu7691对胃癌细胞的体外增殖抑制作用;以流式细胞术考察Hu7691对HGC27细胞周期的影响,采用Western blotting考察Hu7691作用后,细胞内相关蛋白的表达变化;采用HGC27裸小鼠移植瘤模型评价Hu7691的体内抗肿瘤活性。结果Hu7691在HGC27和BGC823细胞模型上能显著抑制肿瘤细胞增殖;引起肿瘤细胞发生细胞周期阻滞,浓度依赖性地下调AKT通路相关蛋白p-PRAS40(T246)、p-GSK3β、p-S6(S235/236)、p-4EBP1(T37/46)及p-4EBP1(S65)的蛋白表达,上调p-AKT(S473)、p-AKT(S308)的表达;下调细胞周期相关蛋白Cyclin D1的表达;在HGC27裸小鼠移植瘤模型中,Hu7691能显著抑制肿瘤生长,并且对小鼠体质量无显著影响。结论新型AKT抑制剂Hu7691通过诱导细胞周期阻滞,发挥对胃癌细胞体内外显著的抗肿瘤活性。OBJECTIVE To investigate the anti-cancer efficacy of a novel AKT inhibitor Hu7691 against gastric cancer cells and its mechanism.METHODS Using human gastric cancer cells HGC27 and BGC823 as in vitro cell models,the SRB method was used to evaluate the in vitro proliferation inhibitory effects of Hu7691 at different concentrations on gastric cancer.The effect of Hu7691 on cell cycle was detected by flow cytometry.Western blotting was performed to determine the change of protein level caused by Hu7691 treatment.The in vivo anti-tumor efficacy was assessed in a human HGC27 gastric cancer xenograft model.RESULTS Hu7691 exhibited significant cytotoxicity in gastric cancer HGC27 and BGC823 cells and induced cell cycle arrest.Hu7691 treatment downregulated the protein expression of AKT pathway related proteins of p-PRAS40(T246),p-GSK3β,p-S6(S235/236),p-4EBP1(T37/46)and p-4EBP1(S65)in a concentration-dependent manner,while it upregulated the expression of p-AKT(S473)and p-AKT(S308),down-regulated the expression of cell cycle related protein Cyclin D1.The anti-cancer efficacy of Hu7691 was validated in the HGC27 xenograft model and had no significant effect on the body weight of the mice.CONCLUSION The novel AKT inhibitor Hu7691 exhibits potent in vitro and in vivo anti-caner efficacy on gastric cancer cells via inducing cell cycle arrest.

关 键 词：AKT抑制剂 Hu7691 胃癌 抗肿瘤活性 周期阻滞 

分 类 号：R965.1[医药卫生—药理学]