基于网络药理学探讨白头翁汤的抗肿瘤作用机制

Study on the anti-tumor mechanism of Baitouweng decoction based on network pharmacology

目的基于网络药理学的方法筛选白头翁汤的有效活性成分,预测其潜在的抗肿瘤靶点,并筛选出与"有效成分-肿瘤靶点"相关的通路,探讨白头翁汤潜在的抗肿瘤作用机制。方法通过中药系统药理学数据库及分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)以及查阅文献,预测并筛选白头翁汤主要活性成分及其对应的靶点。通过治疗靶点数据库(Therapeutic Target Database,TTD)和药物数据库DrugBank收集肿瘤作用的靶点,并与之匹配,获得白头翁汤有效活性成分潜在的抗肿瘤靶点。利用Cytoscape 3.6.0软件构建白头翁汤活性成分-肿瘤作用靶点可视化网络,分析其拓扑结构。通过生物学信息注释数据库(the Database for Annotation,Visualization and Integrated Discovery,DAVID)对靶点基因本体(GO)生物学过程以及京都基因与基因组百科全书(KEGG)信号通路进行分析。结果从白头翁汤中共筛选出具有抗肿瘤作用的有效活性成分35种,其中β-谷甾醇(β-sitosterol)、盐酸巴马汀(palmatine)和槲皮素(quercetin)等是最主要的活性成分,并作用于前列腺素(PG)H1和PGH2,人电压门控型钾离子通道亚家族H成员(KCNH)2和视黄酸受体α(RXRA)等91个潜在的抗肿瘤靶点。同时,白头翁汤可能通过调节肿瘤坏死因子(TNF)信号通路、磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)、低氧诱导因子(HIF)1和血管内皮生长因子等信号通路影响肿瘤细胞增殖、迁移、凋亡、血管生成、基因表达、蛋白质磷酸化和细胞外调节蛋白激酶(ERK)1及ERK2级联反应等生物学过程来发挥抗肿瘤作用。结论中药复方白头翁汤通过多成分、多靶点和多途径的抗肿瘤方式发挥其抗肿瘤作用,这可为深入研究白头翁汤主要成分的抗肿瘤机制提供新的思路和线索。

Objective To screen the effective active components of Baitouweng decoction by the method of network pharmacology, predict its potential anti-tumor targets, screen out the pathways related to active component-tumor target,and explore the potential anti-tumor mechanism of Baitouweng decoction. Methods The main active components and their corresponding targets were predicted and screened by the traditional Chinese medicine system pharmacology database and analysis platform(TCMSP) and literature review. The targets of tumor action were collected and matched using the therapeutic target database(TTD) and drug database DrugBank to obtain potential anti-tumor targets for effective active components of Baitouweng decoction. By using the software Cytoscape 3.6.0, a visual network was formed based on the active components of Baitouweng decoction and the targets of tumor action, and its topology was analyzed. The gene ontology(GO) biological processes and the Kyoto encyclopedia of genes and genomes(KEGG) signaling pathways of the targets were analyzed through the database for annotation, visualization and integrated discovery(DAVID). Results A total of 35 effective active components with anti-tumor effects of Baitouweng decoction were screened out, and among which beta-sitosterol, palmatine and quercetin were the most important ones, acting on 91 potential antitumor targets such as prostaglandin(PG) H1, PGH2, KCNH2 and retinoic acid receptor α(RXRA). Meanwhile, Baitouweng decoction could affect the biological processes such as tumor cell proliferation, migration, apoptosis, angiogenesis, gene expression, protein phosphorylation and the cascade of protein kinases extracellular regulated protein kinase(ERK)1 and ERK2 by regulating tumor necrosis factor(TNF) signaling pathway, phosphatidylinositol 3-kinase(PI3 K)-Protein kinase B(Akt), hypoxia inducible factor(HIF)1 and vascular endothelial growth factor(VEGF) signaling pathways to exert their anti-tumor effects.Conclusion The Chinese herbal compound Baitouweng decoction exerts anti-tumor effect through the anti-tumor method of multi-component, multi-target and multi-channel, which can provide new ideas and clues for further study on the anti-tumor mechanism of the major components of Baitouweng decoction.