基于网络药理学和动物实验探讨大黄酸抗乳腺癌作用与分子机制

Anti-breast Cancer Effect and Molecular Mechanism of Rhein Based on Network Pharmacology and Animal Experiments

目的 通过整合网络药理学和动物实验探讨大黄酸抗肿瘤的作用与分子机制,为进一步深入研究大黄酸联合多柔比星抗乳腺癌的分子机制提供实验依据与理论指导。方法 通过体内构建荷4T1原位移植瘤小鼠模型,考察大黄酸联合多柔比星的抗乳腺癌作用。并利用Pubchem数据库、Swiss Target Prediction数据库、STITCH数据库、TCMSP数据库获取大黄酸成分及作用靶点,运用OMIM、TTD、Genecards等数据库取得乳腺癌的疾病靶点,利用Cytoscape 3.8.2软件构建“药物-成分-疾病-靶点”网络和蛋白质相互作用(protein-protein interaction,PPI)网络,对其进行拓扑学分析,获得潜在共同靶点;基于R软件使用Bioconductor生物信息软件包对共同靶点进行GO功能注释和KEGG富集分析,筛选药物作用于疾病的可能机制。结果 体内药效结果显示大黄酸能增强多柔比星抗乳腺癌作用。经数据库分析获得大黄酸成分作用靶点64个,乳腺癌疾病作用靶点1 839个,药物和疾病交集靶点31个。PPI网络分析以及KEGG通路富集分析显示,多个关键靶蛋白MMP9、CASP3、VEGFA、MAPK8、ESR1等,以及白介素-17、肿瘤坏死因子、细胞增殖与凋亡、雌激素受体等关键信号通路与乳腺癌关系密切。结论 大黄酸可提高多柔比星抗乳腺癌作用,其机制可能与抑制肿瘤血管生长、下调雌激素受体、诱导细胞凋亡、参与肿瘤细胞外基质重塑等有关。

OBJECTIVE To explore the anti-tumor effect and molecular mechanism prediction of rhein by network pharmacology and animal experiments,and provide experimental basis and theoretical guidance for further study of the molecular mechanism of rhein combined with doxorubicin in anti-breast cancer.METHODS The tumor xenograft in mouse model was constructed to investigate the anti-breast cancer effect of rhein combined with doxorubicin.And the Pubchem database,Swiss Target Prediction database,STITCH database,TCMSP database were used to obtain rhein components and action targets,the OMIM,TTD,Genecards and other databases was used to obtain breast cancer disease targets,the"component-disease-target"network and proteinprotein interaction(PPI)network was constructed by Cytoscape 3.8.2 to perform topological analysis,and obtain potential targets;the Bioconductor bioinformatics package based on R software was used for GO functional annotation and KEGG enrichment analysis,to screen for possible mechanisms by which drugs act on diseases.RESULTS The pharmacodynamic results in vivo showed that rhein could enhance the anti-breast cancer effect of doxorubicin.Through database analysis,64 targets of rhein components,1839 targets of breast cancer disease,and 31 targets of drug and disease intersection were obtained.PPI network analysis and KEGG pathway enrichment analysis showed that multiple key target proteins MMP9,CASP3,VEGFA,MAPK8,etc.,as well as key signaling pathways such as interleukin-17,tumor necrosis factor,cell proliferation and apoptosis,were closely related to breast cancer.CONCLUSION Rhein can enhance the anti-breast cancer effect of doxorubicin by inhibiting tumor angiogenesis,down regulating estrogen receptor,inducing apoptosis,and participating in tumor extracellular matrix remodeling.