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  • 李英,崔修亮,张友磊,张国庆.基于药物重定位策略和网络药理学方法筛选肝细胞癌预防药物[J].第二军医大学学报,2019,40(8):879-884    [点击复制]
  • LI Ying,CUI Xiu-liang,ZHANG You-lei,ZHANG Guo-qing.Screening of drugs for hepatocellular carcinoma prevention based on drug repositioning and network pharmacology[J].Acad J Sec Mil Med Univ,2019,40(8):879-884   [点击复制]
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基于药物重定位策略和网络药理学方法筛选肝细胞癌预防药物
李英1,崔修亮2,张友磊3,张国庆1*
0
(1. 海军军医大学(第二军医大学)东方肝胆外科医院药材科, 上海 200438;
2. 海军军医大学(第二军医大学)国家肝癌科学中心, 上海 200438;
3. 海军军医大学(第二军医大学)东方肝胆外科医院肝外二科, 上海 200438
*通信作者)
摘要:
目的 基于药物重定位策略,筛选可用于预防肝细胞癌(HCC)的药物。方法 收集包含肝硬化、低度不典型结节、高度不典型结节和早期HCC等肝脏疾病不同进展阶段的表达谱数据,确定相邻疾病进展阶段的转录组变化,同时收集作用于人肝癌细胞系HepG2的3 927种药物和小分子的基因表达谱,利用基因集富集分析(GSEA)算法分别计算不同药物作用与疾病进展阶段转录组变化相似性,筛选其中负相关药物作为HCC预防的候选药物,并通过构建药物激活子网和通路富集分析等方法研究候选药物的作用机制。结果 分别筛选出对疾病不同进展阶段具有阻碍作用的药物importazole、吡考他胺和紫杉醇,这3种药物对肝硬化到早期HCC的多个疾病阶段均有一定阻断作用,3种药物与疾病进展的基因表达模式呈负相关,通路富集分析结果提示这3种药物通过肿瘤相关通路、p53信号通路、黏附斑、视黄醇代谢等发挥作用。结论 通过药物重定位策略筛选出了HCC预防药物,且结果提示抗血小板治疗可能会预防HCC发生,为后续研究提供了有用线索。
关键词:  药物重定位  肝肿瘤  抗致癌药  网络药理学
DOI:10.16781/j.0258-879x.2019.08.0879
投稿时间:2019-05-25修订日期:2019-07-26
基金项目:国家自然科学基金(81602620),海军军医大学(第二军医大学)精准医学转化应用研究专项(2017JZ52).
Screening of drugs for hepatocellular carcinoma prevention based on drug repositioning and network pharmacology
LI Ying1,CUI Xiu-liang2,ZHANG You-lei3,ZHANG Guo-qing1*
(1. Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Naval Medical University(Second Military Medical University), Shanghai 200438, China;
2. National Center for Liver Cancer, Naval Medical University(Second Military Medical University), Shanghai 200438, China;
3. Department of Hepatic Surgery(Ⅱ), Eastern Hepatobiliary Surgery Hospital, Naval Medical University(Second Military Medical University), Shanghai 200438, China
*Corresponding author)
Abstract:
Objective To screen novel drugs for hepatocellular carcinoma (HCC) prevention based on drug repositioning strategy. Methods We collected the gene expression profiles of tissue samples representing the stepwise carcinogenic process covering 4 stages:cirrhosis, low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN) and early HCC, and identified the gene signatures between two consecutive stages. We also collected the gene expression data of human hepatocellular carcinoma cell lines HepG2 treated by 3 927 drugs and small molecules. The similarity between disease expressions and the drug gene expressions was calculated using gene set enrichment analysis (GSEA) algorithm, and drugs negatively correlated with the disease signatures were selected. Finally, we constructed the activated sub-network and performed pathway enrichment analysis to explore the underlying mechanisms of these drugs. Results We screened out the drugs that could prevent HCC during different stages, and found that importazole, picotamide and paclitaxel exhibited preventive potentials at all stages from cirrhosis to early HCC. The genes affected by these 3 drugs showed inverse expression pattern during HCC development, and pathways such as cancer-related pathway, p53 signaling pathway, focal adhesion and retinol metabolism pathway were enriched. Conclusion Preventive drugs for HCC have been screened through drug repositioning strategy, and our results indicated that antiplatelet therapy may play a role in the prevention of HCC, which provides information for further study.
Key words:  drug repositioning  liver neoplasms  anticarcinogenic agents  network pharmacology