基于药物表达谱模式筛选结肠癌候选治疗药物  

Screening of candidate therapeutic compounds for colon cancer based on a pattern of gene expression profiles

作　　者：王纯忠[1] 杨邵宇[1] 肖慧莲[1] 刘丽娜[2] 王桂平[2] 

机构地区：[1]广州市第一人民医院普通外科,广东广州510380 [2]广州医科大学卫生职业技术学院系统生物与肿瘤研究中心,广东广州510180

出　　处：《中国肿瘤生物治疗杂志》2016年第2期212-217,共6页Chinese Journal of Cancer Biotherapy

基　　金：广东省中医药局建设中医药强省项目(No.20121001)~~

摘　　要：目的:药物表达谱是发现药物新用途的重要模式,本项目探讨药物表达谱模式在结肠癌候选药物筛选中的应用价值。方法:首先,从Pub Med的GEO数据库中获取结肠癌表达谱数据集(No.GSE41258),从美国Memorial Sloan-Kettering癌症中心筛选出53对配对的结肠癌与癌旁正常组织样本数据,采用RMAexpress软件进行质量分析;然后,采用Dchip软件建立结肠癌特征性表达谱;最后通过Connectivity Map(CMAP)进行结肠癌候选化合物的筛选和实验验证。结果:经芯片质量分析,选择36对配对样本进行后续分析;构建了一个由371个基因组成的结肠癌特征性表达谱,其中上调基因94个,下调基因277个;通过CMAP分析,筛选到vorinostat、tanespimycin(17-AAG)等10种候选药物,选择其中一种富集分数较高的药物17-AAG进行验证;后续实验证实17-AAG可有效抑制结肠癌SW480和HT29株细胞的增殖,其作用24和48 h时,SW480细胞的IC50分别为0.73和0.41μmol/L;而HT29细胞的IC50分别为0.72和0.50μmol/L。流式术分析显示,17-AAG可使结肠癌细胞阻滞于G1期。结论:本项目基于药物表达谱模式筛选到多种结肠癌候选药物,揭示药物表达谱模式在药物发现中具有重要意义。Objective： Gene expression profile is an important pattern to discover new uses of the existing drugs. Application value of the gene expression profile in screening of candidate drugs for colon cancer was discussed. Methods： First of all,data set of gene expression profile for colon cancer（ No. GSE41258） was obtained from GEO data bank of Pub Med. Fifty-three paired data of colon cancer and colonic mucosal tissues were selected from Memorial Sloan-Kettering Cancer Center of the United States,and their qualities analyzed with RMA express software. Then a gene expression profile for characteristics of colon cancer was established with Dchip software. Finally candidate compounds for therapy of colon cancer were screened by Connectivity Map（ CMAP） and confirmed by experiments. Results： Thirty-six paired samples were selected through analysis of microarray chips for further research. A gene expression profile for characteristics of colon cancer was composed of 371 genes which include 94 up-regulation genes and 277 down-regulation genes. With analysis of CMAP,10 candidate compounds,including vorinostat,tanespimycin（ 17-AAG） etc,were screened out,in which17-AAG with high enrichment scores was selected for the validation. By the following experiments,it was confirmed that17-AAG can effectively inhibit proliferation of colon cancer SW480 and HT29 cell lines. After treatment of 17-AAG for 24 and 48h,the IC50 values of SW480 cell line were 0. 73 μmol / L and 0. 41 μmol / L respectively,while the IC50 values of HT29 cell line was 0. 72 μmol / L and 0. 5 μmol / L respectively. Analysis of flow cytometry assay showed that 17-AAG could block cell cycle of the colon cancer cells at G1 phase. Conclusion： Multiple candidate therapeutic compounds for colon cancer were identified based on a pattern of gene expression profiles. A pattern of gene expression profiles might be of an important significance in screening of candidate drugs.

关 键 词：基因表达谱 结肠癌 CONNECTIVITY Map 候选治疗药物 

分 类 号：R735.3[医药卫生—肿瘤]