乌梅丸治疗乳腺癌肺转移的药理机制

Pharmacological Mechanism of Wumeiwan in Treating Lung Metastasis of Breast Cancer

目的:通过对乌梅丸进行网络药理学分析和实验验证,探讨该方治疗乳腺癌肺转移的潜在靶点及作用机制。方法:通过TCMSP数据库建立乌梅丸有效成分和靶点数据集,GeneCards数据库及OMIM数据库建立乳腺癌肺转移相关靶点数据集,并将中药靶点和疾病靶点数据相匹配。通过Cytoscape 3.6.0软件进行中药-活性成分-治疗靶点的网络分析,STRING数据库分析关键靶点蛋白间的相互作用关系。利用生物学信息注释数据库进行靶点基因本体(GO)分析以及京都基因与基因组百科全书(KEGG)信号通路富集分析。结果:共发现乌梅丸治疗乳腺癌肺转移有108个可能的重要靶点,包括白细胞介素-6(IL6),半胱氨酸蛋白酶-3(CASP3),血管内皮生长因子A(VEGFA),表皮生长因子受体(EGFR),丝裂原活化蛋白激酶8(MAPK8)等,GO富集分析得到乳腺癌肺转移相关的29个细胞组分(CC),1 218个生物学过程(BP)及125个分子功能(MF),KEGG富集分析得到与乳腺癌肺转移相关的118条通路(P<0.05),包括MAPK信号通路、细胞凋亡途径等。体外实验表明,乌梅丸的有效成分肉桂醛具有诱导乳腺癌MCF7细胞凋亡、抑制增殖和迁移的作用,一定程度验证了网络药理学的预测结果。结论:乌梅丸对乳腺癌肺转移的治疗作用是多靶点、多途径、多机制的,本研究结果为乌梅丸的临床应用提供了一定证据支持。

Objective:To explore the potential target and mechanism of Wumeiwan in the treatment of lung metastasis of breast cancer by network pharmacological analysis and experimental verification. Method:The databases of active ingredients and targets of Wumeiwan were established through Traditional Chinese Medicine Systems Pharmacology(TCMSP)Database and Analysis Platform,and the targets of lung metastasis of breast cancer were established through the GeneCards database and Online Mendelian Inheritance in Man(OMIM)database,and the data of Chinese medicine targets and disease targets were matched. Cytoscape 3.6.0 software was used to establish the network analysis of traditional Chinese medicine-active ingredients-therapeutic targets,and the interaction relationship between key target proteins was analyzed by STRING database. Target gene ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) signal pathway enrichment analysis were performed by using the Biological Information Annotation Database. Result: A total of 108 possible important targets for Wumeiwan in the treatment of lung metastasis of breast cancer were found,including interleukin 6(IL6),cysteine aspartate-specific protease-3(CASP3),vascular endothelial growth factor A(VEGFA),epidermal growth factor receptor(EGFR),mitogen-activated protein kinase(MAPK8),and others.GO enrichment analysis yielded 29 cell components(CC),1 218 biological processes(BP)and 125 molecular functions(MF)related to lung metastasis of breast cancer,and KEGG enrichment analysis yielded 118 pathways related to lung metastasis of breast cancer(P<0.05),including MAPK signaling pathway and apoptosis pathway.In vitro experiments showed that cinnamaldehyde,the active ingredient of Wumeiwan,could induce apoptosis,inhibit proliferation and migration of MCF7 cells,partially validating the predicted results of network pharmacology to a certain extent. Conclusion:The therapeutic effect of Wumeiwan on lung metastasis of breast cancer may be multi-target,multi-pathway and multi-mechanism. The results of this study provide more evidence for the clinical application of Wumeiwan.