基于网络药理学与组分配伍理论探讨鳖甲-莪术有效组分协同抗三阴性乳腺癌的作用及机制验证  

The synergistic effect and mechanism verification of effective componentsof Biejia-Ezhu against triple-negative breast cancer based on networkpharmacology and component compatibility theory

作　　者：冯豆豆 骆小珊 蒙雁云 赵晶哲 朱久龙 黄雅珍 谢青 凌湘力 谢甦 FENG Dou-dou;LUO Xiao-shan;MENG Yan-yun;ZHAO Jing-zhe;ZHU Jiu-long;HUANG Ya-zhen;XIE Qing;LING Xiang-Li;XIE Su(Clinical Medical College,Guizhou Medical University,Guiyang 550004,China;TCM-Integrated Hospital of Southern Medical University,Guangzhou 510000,China;Affiliated Hospital of Guizhou Medical University,Guiyang 550004,China)

机构地区：[1]贵州医科大学临床医学院,贵州贵阳550004 [2]南方医科大学附属中西医结合医院,广东广州510000 [3]贵州医科大学附属医院,贵州贵阳550004

出　　处：《中国药理学通报》2025年第5期950-959,共10页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 2460883);凌湘力全国名中医传承工作室建设项目(国中医药办人教函[2022]245号);贵州省科技计划项目(黔科合基础-ZK[2022]一般442),[2024]一般204);贵州省中医药管理局民族医药科学技术研究课题(No QZYY-2023-001)。

摘　　要：目的探究鳖甲-莪术抗三阴性乳腺癌(triple negative breast cancer,TNBC)的有效组分配伍及潜在作用机制并进行实验验证。方法利用TCMSP、Swiss Target Prediction获得鳖甲-莪术有效成分及作用靶点;OMMI、GeneCards数据库获取TNBC的疾病靶点;STRING数据库构建PPI网络;DAVID数据库进行GO、KEGG通路富集分析。Cytoscape3.9.1软件构建“药物-成分-靶点-疾病”网络,筛选关键靶点与成分进行分子对接,进一步对关键组分配伍及靶点进行体外实验验证。结果①鳖甲-莪术药对中筛选出71个有效成分,药物与疾病相关靶点146个,通过KEGG分析得出113条信号通路。鳖甲-莪术的71个潜在活性成分主要作用于mTORC1、ULK1、TNF、EGFR等关键靶点。分子对接结果显示,甘氨酸和姜黄素为鳖甲-莪术的关键活性成分,均对关键靶蛋白mTORC1和ULK1有较强的对接活性。②体外实验发现,甘氨酸联合姜黄素明显抑制TNBC细胞的增殖和克隆形成(P<0.05),抑制核心靶点EGFR的表达,上调自噬活性标志蛋白LC3Ⅱ/Ⅰ表达、下调通路蛋白mTORC1、p-mTOR、p-ULK1蛋白表达、促进通路蛋白ULK1表达(P<0.05)。结论鳖甲-莪术药对抗三阴性乳腺癌关键组分配伍是甘氨酸-姜黄素,其作用机制可能与调控mTORC1/ULK1信号通路促进细胞自噬相关。Aim To explore the compatibility and potential mechanism of effective components of Biejia-Ezhu against triple negative breast cancer(TNBC)and verify it by experiments.Methods Effective components and targets of Biejia-Ezhu were obtained by TCMSP and Swiss Target Prediction.Disease targets of TNBC were obtained from OMMI and GeneCards databases.The PPI network was constructed using STRING database.GO and KEGG path enrichment analysis was performed using DAVID database.Cytoscape3.9.1 software was used to construct the“drug-component-target-disease”network,screen key targets and components for molecular docking,and further verify the compatibility of key components and targets in vitro.Results①A total of 71 effective components were identified in the Biejia-Ezhu drug pair.There were 146 drug targets associated with the disease.A total of 113 signaling pathways were identified by KEGG analysis.The 71 potential active components of Biejia-Ezhu mainly acted on key targets such as mTORC1,ULK1,TNF,EGFR,ESR1,STAT3,HIF1A,and PTGS2.Molecular docking results showed that glycine and curcumin were the key active components of Biejia-Ezhu,and both had strong docking activity against key target proteins mTORC1 and ULK1.②The results of in vitro experiment showed that glycine combined with curcumin significantly inhibited the proliferation and clonal formation ability of TNBC cells(P<0.05),up-regulated the expression of autophagy marker LC3Ⅱ/Ⅰ,down-regulated the expression of EGFR,down-regulated the expression of pathway protein mTORC1,p-mTOR,p-ULK1,and promoted the expression of pathway protein ULK1(P<0.05).Conclusion The key component of Biejia-Ezhu against triple-negative breast cancer is glycine-curcumin,the mechanism of which may be related to the regulation of the mTORC1/ULK1 signaling pathway to promote autophagy.

关 键 词：鳖甲-莪术药对 三阴性乳腺癌 组分配伍 自噬 mTORC1/ULK1信号通路 作用机制 

分 类 号：R282.71[医药卫生—中药学] R289.1[医药卫生—中医学] R319R392R737.9