基于靶方/靶药/靶标关联分析探讨肺癌脑转移之中药配伍规律

Exploration on Compatibility of Traditional Chinese Medicine in Lung Cancer Brain Metastasis Based on“Target Prescription/Target Drug/Target” Correlation Analysis

目的通过数据挖掘及网络药理学手段,从靶方/靶药/靶标关联分析中医药治疗肺癌脑转移的组方用药规律,为中药治疗肺癌脑转移提供指导。方法从中国知网、万方、维普数据库中筛选出近30年有关中医药治疗肺癌脑转移的文献,把所收集的方剂录入中医传承辅助平台V2.5中,同时采用软件集成的数据分析方法进行数据挖掘,对所筛选出的方剂进行组方用药规律分析。运用TCMSP检索高频药对入脑成分,经瑞士目标预测网站获得对应靶点,与Genecards、OMIM、Disgenet数据库筛选出“肺癌”“脑转移”的靶点取交集,使用Cytoscape3.7.2构建“药物-疾病-成分-靶点”的网络图,在STRING数据库中构建关键靶点的PPI网络,并以Degree值等条件进行筛选,最终得到高频药对治疗肺癌脑转移的核心靶点的相关信息。再对关键靶点用R语言进行GO富集和KEGG通路富集分析,在KEGG网站中标记主要通路的干预位点。根据以上结果,从靶方/靶药/靶标关联分析中医药治疗肺癌脑转移的组方用药规律。结果筛选出治疗肺癌脑转移的方剂42首,其中涉及中药162味,用药频次≥8次的中药20个,出现频度≥9次的药对9组,经辅助平台分析得出演化的新处方9张。黄芪-石菖蒲作为核心药对,发现作用于肺癌脑转移的关键靶点共64个,核心靶点14个,GO功能分析发现与蛋白酪氨酸激酶信号通路、无机物反应等生物过程有关,KEGG通路富集分析出重要通路15条。结论肺癌脑转移的核心病机虚实夹杂,以虚、痰、瘀、毒为主,治疗多以益气养阴、化痰通络、活血化瘀、清热解毒为法。黄芪-石菖蒲高频药对治疗肺癌脑转移的主要靶点为EGFR、ERBB2、AKT1、STAT3、SRC、MTOR等,主要通过影响癌症的通路、EGFR-TKI的耐药性相关通路、癌症中的小分子核糖核酸、MAPK信号通路、IL-17通路、RPTKs信号通路等发挥作用。中医药治疗肺癌脑转移的靶方为桃红四物汤合三虫散加减,靶症药可选择白术、茯苓、丹参、天麻、麦冬等,靶标药可选择黄芪、石菖蒲、白花蛇舌草、猫爪草、莪术、蟾酥、壁虎等。

Objective By means of data mining and network pharmacology,the prescription medication rules of traditional Chinese medicine in the treatment of lung cancer brain metastasis was analyzed from the correlation of target prescription/target drug/target,providing guidance for the treatment of lung cancer brain metastasis by traditional Chinese medicine.Methods The literatures about TCM treatment of lung cancer brain metastasis in recent 30 years were screened out from CNKI,Wanfang and VIP databases,and the collected prescriptions were input into the TCM inheritance auxiliary platform V2.5.At the same time,the data analysis method of software integration was used for data mining,and the prescription law of selected prescriptions was analyzed.TCMSP was used to retrieve the components of high-frequency drug pairs entering the brain,and the corresponding target sites were obtained through the Swiss target prediction website.The target sites of“lung cancer”and“brain metastasis”were screened out and intersected with Genecards,OMIM and Disgenet databases.The network diagram of“drug-disease-component-target”was constructed with Cytoscape3.7.2.PPI network of key targets was constructed in STRING database,and screened by Degree value and other conditions.Finally,the relevant information about the core targets of high-frequency drugs in the treatment of lung cancer brain metastasis was obtained.Then key targets were analyzed for GO enrichment and KEGG pathway enrichment using R language,and intervention sites of main pathways were marked in KEGG website.Based on the above results,the association between target prescription/target drug/target was analyzed to analyze the prescription medication rule of traditional Chinese medicine in the treatment of lung cancer brain metastasis.Results A total of 42 prescriptions for the treatment of lung cancer brain metastasis were screened,including 162 Chinese medicines,20 Chinese medicines with frequency≥8 times,9 drug pairs with frequency≥9 times and 9 new prescriptions were obtained by auxiliary platform analysis.As the core drug pair,Huangqi(Astragali Radix)and Shichangpu(Acori Tatarinowii Rhizoma)were found to act on 64 key targets of lung cancer brain metastasis,including 14 core targets.GO functional analysis showed that they were related to protein tyrosine kinase signaling pathway,inorganic reaction and other biological processes.KEGG pathway enrichment analysis revealed 15 important pathways.Conclusion The core pathogenesis of brain metastasis of lung cancer is mixed with deficiency and excess,with deficiency,phlegm,blood stasis and toxin as the main treatment methods,such as tonifying Qi and nourishing Yin,resolving phlegm and clearing collaterals,activating blood stasis,clearing heat and detoxifying.The main targets of Huangqi(Astragali Radix)and Shichangpu(Acori Tatarinowii Rhizoma)in the treatment of lung cancer brain metastasis are EGFR,ERBB2,AKT1,STAT3,SRC,MTOR,etc.It mainly plays a role by influencing cancer pathways,drug-resistance related pathways of EGFR-TKI,small molecular RNA in cancer,MAPK signaling pathway,IL-17 signaling pathway and RPTKs signaling pathway,etc.In the treatment of lung cancer brain metastasis with traditional Chinese medicine,the target prescription is Taohong Siwu Decoction(桃红四物汤)and Sanchu Powder(三虫散),the target drugs can be Baizhu(Atractylodis Macrocephalae Rhizoma),Fuling(Poria),Danshen(Salviae Miltiorrhizae Radix Et Rhizoma),Tianma(Gastrodiae Rhizoma)and Maidong(Ophiopogonis Radix),etc.,and the target drugs can be Huangqi(Astragali Radix),Shichangpu(Acori Tatarinowii Rhizoma),Baihuasheshecao(Hedyotidis Diffusae Herba),Maozhuacao(Ranunculi Ternati Radix),Ezhu(Curcumae Rhizoma),Chansu(Bufonis Venenum),Bihu(gecko),etc.