PI3Ks新型抑制剂NVP-BEZ235对食管鳞癌的抑制作用  

Inhibitory Effect of a Novel PI3Ks Inhibitor NVP-BEZ235 on EsophagealSquamous Cell Carcinoma

作　　者：姚佳仪 王斯琦 钱玉兰[1] 孙晓鸣 马赛 杨薇[2] 郭冰[2] 杨中 查良英 YAO Jiayi;WANG Siqi;QIAN Yulan;SUN Xiaoming;MA Sai;YANG Wei;GUO Bing;YANG Zhong;ZHA Liangying(The First Affiliated Hospital of Soochow University,Suzhou,Jiangsu,China 215006;The Fifth People's Hospital of Suzhou,Suzhou,Jiangsu,China 215131;Suzhou Guangji Hospital,Suzhou,Jiangsu,China 215131;The Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou,Jiangsu,China 215008;The People's Hospital of Suzhou New District,Suzhou,Jiangsu,China 215129)

机构地区：[1]苏州大学附属第一医院,江苏苏州215006 [2]江苏省苏州市第五人民医院,江苏苏州215131 [3]江苏省苏州市广济医院,江苏苏州215131 [4]南京医科大学附属苏州医院,江苏苏州215008 [5]江苏省苏州高新区人民医院,江苏苏州215129

出　　处：《中国药业》2023年第9期28-32,共5页China Pharmaceuticals

基　　金：国家自然科学基金[82002519];江苏省苏州市科学技术局科技发展计划-民生科技项目[SYS2020168]。

摘　　要：目的探讨磷脂酰肌醇3-激酶(PI3Ks)新型抑制剂NVP-BEZ235(Dactolisib)对食管鳞癌体内外模型的抑制作用,为食管鳞癌的靶向治疗提供参考。方法采用免疫印迹(Western blot)法检测食管鳞癌细胞系中磷脂酰肌醇3-激酶调节亚基p85α(PI3K-p85α)蛋白的表达情况;对食管鳞癌的细胞系分别给予0,1,4,8,16,32,64,128 nmol/L浓度的NVP-BEZ235,采用MTT法检测生长情况,计算细胞生存率及半数抑制浓度(IC50);对PI3K-p85α高表达及低表达的食管鳞癌细胞系分别予10 nmol/L NVP-BEZ235,观察细胞集落形成情况;建立裸鼠皮下移植瘤模型,评估NVP-BEZ235的体内治疗效果。结果PI3K-p85α高表达的食管鳞癌细胞系KYSE30,KYSE70,KYSE510,TE1对NVP-BEZ235更敏感,IC50分别为4.92,5.43,4.76,7.78 nmol/L;而PI3K-p85α低表达的细胞系KYSE150,KYSE180,KYSE270,KYSE450对NVP-BEZ235的敏感度较低,IC50分别为13.21,18.44,20.37,48.45 nmol/L。加入10 nmol/L NVP-BEZ235进行的集落形成实验结果相似,KYSE30,KYSE70,KYSE510,TE1的集落数目少于KYSE150,KYSE180,KYSE270,KYSE450的集落数目。在裸鼠皮下移植瘤模型中,较低浓度(10 mg/kg)的NVP-BEZ235即可抑制食管鳞癌皮下移植瘤的生长。结论NVP-BEZ235对食管鳞癌细胞系和裸鼠移植瘤都有明显的抑制作用,在PI3K-p85α高表达的食管鳞癌细胞系中抑制效果更明显,在食管鳞癌中具有一定靶向性,可为后期的临床试验提供参考。Objective To investigate the inhibitory effect of NVP-BEZ235(Dactolisib),a novel phosphatidylinositol 3-kinase(PI3Ks)inhibitor,on esophageal squamous cell carcinoma(ESCC)in vivo and in vitro,and to provide a reference for targeted therapy of ESCC.Methods The expression of phosphatidylinositol 3-kinase regulatory subunit p85α(PI3K-p85α)protein in ESCC cell lines was detected by Western blot.The ESCC cell lines were treated with different concentrations of NVP-BEZ235(0,1,4,8,16,32,64,and 128 nmol/L).The growth of cells was detected by the MTT method,and the cell survival rate and 50%inhibitory concentration(IC50)were calculated.ESCC cell lines with high and low expression of PI3K-p85αwere treated with 10 nmol/L NVP-BEZ235 respectively,and the formation of cell colonies was observed.The in vivo therapeutic effect of NVP-BEZ235 was evaluated by establishing a subcutaneous tumor xenograft model in nude mice.Results The ESCC cell lines KYSE30,KYSE70,KYSE510,and TE1 with high expression of PI3K-p85αshowed higher sensitivity to NVP-BEZ235 with IC50 values of 4.92,5.43,4.76,and 7.78 nmol/L,respectively.The ESCC cell lines KYSE150,KYSE180,KYSE270,and KYSE450 with low expression of PI3K-p85αshowed lower sensitivity to NVP-BEZ235 with IC50 values of 13.21,18.44,20.37,and 48.45 nmol/L,respectively.Similar results were obtained in the colony formation experiment with the treatment of 10 nmol/L of NVP-BEZ235,and the colony number of KYSE30,KYSE70,KYSE510,and TE1 was fewer than that of KYSE150,KYSE180,KYSE270,and KYSE450.In a nude mouse model of subcutaneous tumor xenograft,a lower concentration(10 mg/kg)of NVP-BEZ235 could inhibit the growth of subcutaneous tumor xenograft of ESCC.Conclusion NVP-BEZ235 showed obvious inhibitory effect on ESCC cell lines and tumor xenograft in nude mice.The inhibitory effect of NVP-BEZ235 is more obvious in ESCC cell lines with high expression of PI3K-p85α,indicating the target ability of ESCC,which provides a reference for the future clinic trials.

关 键 词：食管鳞癌 NVP-BEZ235 磷脂酰肌醇3-激酶调节亚基p85α 靶向治疗 

分 类 号：R965[医药卫生—药理学] R979.1[医药卫生—药学]