基于网络药理学对黄连抗结直肠癌作用机制的分析

Analysis on Mechanism of Coptis Chinensis Against Colorectal Cancer Based on Network Pharmacology

目的基于网络药理学分析方法探讨黄连抗结直肠癌的物质基础和作用机制。方法通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)、中医药整合药理学研究平台(Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine,TCMIP)及文献检索收集黄连的主要活性成分,并利用PubChem得到其活性成分的结构信息。采用SwissTargetPrediction数据库检索活性成分作用靶点,在GeneC ards和Open Targets数据库检索结直肠癌疾病相关靶点,并与活性成分靶点取交集作为黄连治疗结直肠癌的潜在作用靶点,导入Cytoscape构建黄连活性成分-结直肠癌疾病靶点网络图。利用STRING构建靶蛋白互作网络。根据拓扑分析筛选黄连治疗结直肠癌的关键药效成分与核心靶点。应用DAVID(Database for Annotation,Visualization and Integrated Discovery)数据库对核心治疗靶点进行GO生物学功能及KEGG通路富集分析。结果黄连62个活性成分通过调控91个结直肠癌相关的疾病靶点,产生了134对化合物-靶点关系,其中黄酮醇类(如槲皮素)和生物碱类(如小檗碱)均发挥了中药作用,参与了体内细胞对化学压力的反应、氧化应激、磷酸化、蛋白激酶B信号传导等生物过程,干预PI3K-AKT、蛋白聚糖、Ras、Rap1、ErbB、HIF-1、FoxO、VEGF、花生四烯酸代谢等信号通路发挥抗结直肠癌的作用。结论黄连中的黄酮醇类和生物碱类等多成分,可通过多靶点、多通路协同发挥抗结直肠癌的作用,CA1、CA12、CA2、CA9、AKT1、EGFR、PTGS2和SRC等可能是其核心治疗靶点,PI3K-AKT、Ras、Rap1和VEGF等可能是其主要作用通路。

Objective To explore the material basis and mechanism of Coptis chinensis against colorectal cancer based on network pharmacology. Methods The main active components of Coptis chinensis were retrieved through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Integrative Pharmacologybased Research Platform of Traditional Chinese Medicine. The structural information of active components was obtained through PubChem. Targets of active ingredients were searched by the SwissTargetPrediction database, while the disease targets related to colorectal cancer were searched on GeneCards and Open Targets databases. The intersection of the active ingredient targets and the disease target was taken as a potential target for the treatment of colorectal cancer, a disease and target network of the active ingredient of Coptis chinensis-colorectal cancer was established by Cytoscape.The network of protein-protein interactions was established by STRING. The key efficacy components and core targets of Coptis chinensis for the treatment of colorectal cancer were selected based on the topological analysis. The GO biological function and KEGG pathway enrichment analysis of the core therapeutic targets were performed using the DAVID database. Results The 62 active components ingredients of Coptis chinensis produced 134 pairs of compound-target relationship by regulating 91 colorectal cancer-related disease targets. Among them, flavonols, such as quercetin, and alkaloids, such as berberine, produced a marked effect in the treatment of colorectal cancer. They participated in biological processes, including cells respond to the chemical pressure, oxidative stress, phosphorylation, protein kinase B signaling, and they interfered with signaling pathways including PI3 K-AKT, proteoglycans, Ras, Rap1, ErbB, HIF-1,FoxO, VEGF, arachidonic acid metabolism to produce the anti-colorectal cancer effect. Conclusion The flavonols and alkaloids in Coptis chinensis had a synergistic anti-colorectal cancer effect through multiple targets and pathways. CA1,CA12, CA2, CA9, AKT1, EGFR, PTGS2 and SRC might be the core therapeutic targets, while PI3 K-Akt, Ras, Rap1 and VEGF might be the main pathways.