摘要
运用网络药理学和分子对接技术及动物实验探究黄芪-莪术-蚤休角药配伍治疗结直肠癌(colorectal cancer,CRC)的潜在机制,并以原位移植瘤裸鼠模型对核心靶点进行验证。在TCMSP等数据库检索黄芪-莪术-蚤休角药活性成分,通过PubChem、SwissTargetPrediction、TTD、DrugBank数据库获得药物及疾病相关靶点并取交集靶点导入STRING数据库进行蛋白质相互作用(protein-protein interaction,PPI)分析,在DAVID数据库进行基因功能注释(Gene Ontology,GO)和京都基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。运用AutoDock Vina对角药活性成分与核心靶点进行分子对接和结合能力预测。构建原位移植瘤裸鼠模型,验证黄芪-莪术-蚤休角药对裸鼠肿瘤生长、转移及肿瘤组织中核心靶点蛋白磷酸化的影响。网络药理学分析结果得到黄芪-莪术-蚤休角药中包括槲皮素(quercetin)、姜黄素(curcumin)、β-蜕皮甾酮(β-ecdysone)等9个核心成分;关键靶点涉及AKT1(protein kinase B)、MAPK3(mitogen-activated protein kinase 3)、MAPK1(mitogen-activated protein kinase 1)、EGFR(epidermal growth factor receptor)等,初步表明黄芪-莪术-蚤休角药可能通过PI3K-AKT、MAPK及其他信号通路来调节肿瘤细胞的增殖、凋亡、迁移和血管生成等生物学过程,从而在CRC治疗中发挥作用。分子对接结果表明9个核心成分与靶蛋白AKT1、MAPK3均有强烈的结合能力。动物实验结果表明,黄芪-莪术-蚤休角药能明显降低结肠癌裸鼠模型原位瘤的体积和肝转移灶数并显著降低AKT1、MAPK3的磷酸化,其干预结肠癌的机制可能与激活PI3K-AKT、MAPK信号通路最为相关。该研究为黄芪-莪术-蚤休角药的临床应用于治疗CRC提供科学依据,也为角药的现代化研究提供思路。
The present study explored the underlying mechanism of Astragali Radix-Curcumae Rhizoma-Paridis Rhizoma(AR-CR-PR) in the treatment of colorectal cancer(CRC) by network pharmacology and molecular docking and animal tests and verified the core targets based on the orthotopic transplantation model in nude mice.The active components of AR-CR-PR were retrieved from databases such as TCMSP.The targets of drugs and the disease were obtained from PubChem,SwissTargetPrediction,TTD,and DrugBank,and the intersection targets were imported into STRING for the analysis of the protein-protein interaction(PPI).Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses were performed through DAVID.AutoDock Vina was used to perform molecular docking and binding ability prediction between the active components and the core targets.The effects of AR-CR-PR on tumor growth,metastasis,and phosphorylation of core target proteins in tumor tissues based on the orthotopic transplantation model in nude mice.As revealed by network pharmacology,AR-CR-PR contained nine core components,such as quercetin,curcumin,and β-ecdysone,and the key targets included protein kinase B(AKT1),mitogen-activated protein kinase 3(MAPK3),MAPK1,and epithelial growth factor receptor(EGFR),which was indicated that the anti-CRC effect of AR-CR-PR was presumedly achieved by regulating tumor cell proliferation,apoptosis,migration,and angiogenesis through PI3 K-AKT,MAPK and other signaling pathways.The results of molecular docking showed that the nine core components had strong binding abilities to AKT1 and MAPK3.The results in vivo showed that AR-CR-PR could reduce the volume of the orthotopic tumor,inhibit liver metastasis,and decrease the phosphorylation of AKT1 and MAPK3 in the CRC model.The mechanism of AR-CR-PR in the intervention of CRC may be related to the activation of PI3 K-AKT and MAPK signaling pathway.This study provides a scientific basis for the clinical application of AR-CR-PR in the treatment of CRC and ideas for modern research on AR-CR-PR.
作者
梁研
孙若岚
刘夫艳
刘甜甜
关汉卿
唐德才
LIANG Yan;SUN Ruo-lan;LIU Fu-yan;LIU Tian-tian;GUAN Han-qing;TANG De-cai(School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China)
出处
《中国中药杂志》
CAS
CSCD
北大核心
2022年第3期776-785,共10页
China Journal of Chinese Materia Medica
基金
国家自然科学基金面上项目(81873021)
江苏省中医药科技发展专项(2020ZX01)
江苏省研究生科研创新计划项目(KYCX211763)。
关键词
黄芪-莪术-蚤休角药
结直肠癌
网络药理学
分子对接
Astragali Radix-Curcumae Rhizoma-Paridis Rhizoma
colorectal cancer
network pharmacology
molecular docking