基于网络药理学探究知柏地黄丸治疗乳腺癌内分泌耐药的作用机制

Study on the mechanism of Zhibai Dihuang Pills in treatment of endocrine resistance in breast cancer based on network pharmacology

目的 运用网络药理学技术探究知柏地黄丸治疗乳腺癌内分泌耐药的活性成分、潜在靶点和作用机制。方法 通过TCMSP数据库、TCM-ID数据库和BATMAN-TCM数据库,筛选知柏地黄丸的有效活性成分和作用靶点,利用GeneCards数据库、OMIM数据库、TTD数据库和GEO数据库检索获得乳腺癌内分泌治疗耐药的相关靶基因,并与活性成分作用靶点取交集得到共同靶点;通过String 11.5数据库构建知柏地黄丸治疗乳腺癌内分泌耐药的蛋白质互作(PPI)网络,并借助Cytoscape 3.8.2软件的CytoNCA插件筛选核心靶点;通过Metascape基因功能注释分析工具对交集靶点进行基因本体(GO)和京都基因组百科全书(KEGG)通路富集分析,使用Cytoscape 3.8.2软件构建药物活性成分–靶点–通路相互作用网络,获取核心活性成分。结果 共筛选出知柏地黄丸活性成分80个,与疾病的交集靶点117个,主要涉及肿瘤蛋白p53(TP53)、蛋白激酶B1(Akt1)、肿瘤坏死因子(TNF)、白细胞介素-6(IL6)、雌激素受体1(ESR1)、丝裂原活化蛋白激酶1(MAPK1)等。KEGG通路富集分析显示磷脂酰肌醇3-激酶(PI3K)/Akt、MAPK、核因子-κB(NF-κB)、雌激素等信号通路可能是知柏地黄丸治疗乳腺癌内分泌耐药的关键信号通路,由药物活性成分–靶点–通路网络得出槲皮素、山柰酚、脱水淫羊藿素、β-谷甾醇、薯蓣皂苷元等是发挥作用的核心活性成分。结论 知柏地黄丸中的槲皮素、山柰酚、脱水淫羊藿素、β-谷甾醇、薯蓣皂苷元等核心活性成分,能够作用于TP53、Akt1、TNF、IL-6、ESR1、MAPK1等多个关键靶点,调节PI3K-Akt、MAPK、NF-κB、雌激素等信号通路,发挥治疗乳腺癌内分泌耐药的作用。

Objective To explore the active ingredients,potential targets and mechanism of action of Zhibai Dihuang Pills in treatment of endocrine drug resistance in breast cancer by network pharmacology.Methods Through TCMSP database,TCM-ID database and BATMAN-TCM database,the active ingredients and targets of Zhibai Dihuang Pills was screened.And the targets related to drug resistance of breast cancer endocrine therapy were retrieved by GeneCards database,OMIM database,TTD database and GEO database.The intersection of component targets and disease targets was used to obtain common targets.The protein-protein interaction network of Zhibai Dihuang Pills for the treatment of endocrine resistance of breast cancer was constructed by String 11.5 database,and the core targets were screened by CytoNCA plug-in of Cytoscape 3.8.2 software.The GO and KEGG pathway enrichment analysis of intersection targets was performed by Metascape gene function annotation analysis tool.The interaction network of active ingredienttarget-pathway was constructed by Cytoscape 3.8.2 software to obtain the core active ingredients.Results A total of 80 active components of Zhibai Dihuang Pills were screened,and 117 intersecting targets with diseases were screened,mainly involving TP53,Akt1,TNF,IL-6,ESR1,MAPK1 and so on.KEGG pathway enrichment analysis showed that PI3K/Akt,MAPK,NF-κB and estrogen may be the key signal pathways of Zhibai Dihuang Pills in the treatment of breast cancer endocrine resistance.Quercetin,kaempferol,dehydrated icariin,β-sitosterol and diosgenin are the core active components from the drug active component-targetpathway network.Conclusion Core active ingredients such as quercetin,kaempferol,Anhydroicaritin,β-sitosterol and diosgenin in Zhibai Dihuang Pills may affect the signaling pathways of PI3K/Akt,MAPK,NF-κB and estrogen by acting on multiple targets such as TP53,Akt1,TNF,IL-6,ESR1 and MAPK1,which plays a role in the treatment of breast cancer endocrine resistance.