Wang Yan, Zhang Yunwu, Wang Yujia, Shu Xinyao, Lu Chaorui, Shao Shiliang, Liu Xingting, Yang Cheng, Luo Jingsong, Du Quanyu
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
Front Chem. 2021 Jun 9;9:682862. doi: 10.3389/fchem.2021.682862. eCollection 2021.
In recent years, the incidence and mortality rates of non-small cell lung cancer (NSCLC) have increased significantly. Shan Ci Gu is commonly used as an anticancer drug in traditional Chinese medicine; however, its specific mechanism against NSCLC has not yet been elucidated. Here, the mechanism was clarified through network pharmacology and molecular docking. The Traditional Chinese Medicine Systems Pharmacology database was searched for the active ingredients of Shan Ci Gu, and the relevant targets in the Swiss Target Prediction database were obtained according to the structure of the active ingredients. GeneCards were searched for NSCLC-related disease targets. We obtained the cross-target using VENNY to obtain the core targets. The core targets were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins database, and Cytoscape software was used to operate a mesh chart. R software was used to analyze the Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The core targets and active compounds were molecularly docked through Auto-Dock Vina software to predict the detailed molecular mechanism of Shan Ci Gu for NSCLC treatment. We did a simple survival analysis with hub gene to assess the prognosis of NSCLC patients. Three compounds were screened to obtain 143 target genes and 1,226 targets related to NSCLC, of which 56 genes were related to NSCLC treatment. Shan Ci Gu treatment for NSCLC involved many BPs and acted on main targets including epidermal growth factor receptor (EGFR), ESR1, and SRC through signaling pathways including the endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways. Shan Ci Gu might be beneficial for treating NSCLC by inhibiting cell proliferation and migration. Molecular docking revealed that the active compounds β-sitosterol, stigmasterol, and 2-methoxy-9,10-dihydrophenanthrene-4,5-diol had good affinity with the core target genes (EGFR, SRC, and ESR1). Core targets included EGFR, SRC, ESR1, ERBB2, MTOR, MCL1, matrix metalloproteinase 2 (MMP2), MMP9, KDR, and JAK2. Key KEGG pathways included endocrine resistance, EGFR tyrosine kinase inhibitor resistance, ErbB signaling, PI3K-Akt signaling, and Rap1 signaling pathways. These core targets and pathways have an inhibitory effect on the proliferation of NSCLC cells. Shan Ci Gu can treat NSCLC through a multi-target, multi-pathway molecular mechanism and effectively improve NSCLC prognosis. This study could serve as a reference for further mechanistic research on wider application of Shan Ci Gu for NSCLC treatment.
近年来，非小细胞肺癌（NSCLC）的发病率和死亡率显著上升。山慈菇是传统中药中常用的抗癌药物；然而，其抗NSCLC的具体机制尚未阐明。在此，通过网络药理学和分子对接阐明了该机制。在中国传统医学系统药理学数据库中搜索山慈菇的活性成分，并根据活性成分的结构在瑞士靶点预测数据库中获取相关靶点。在GeneCards中搜索NSCLC相关疾病靶点。我们使用VENNY获得交叉靶点以得到核心靶点。将核心靶点导入检索相互作用基因/蛋白质的搜索工具数据库，并使用Cytoscape软件操作网状图。使用R软件分析基因本体生物学过程（BP）和京都基因与基因组百科全书（KEGG）通路富集。通过Auto-Dock Vina软件对核心靶点和活性化合物进行分子对接，以预测山慈菇治疗NSCLC的详细分子机制。我们对枢纽基因进行了简单的生存分析，以评估NSCLC患者的预后。筛选出三种化合物，获得143个靶基因和1226个与NSCLC相关的靶点，其中56个基因与NSCLC治疗相关。山慈菇治疗NSCLC涉及许多生物学过程，并通过包括内分泌抵抗、表皮生长因子受体（EGFR）酪氨酸激酶抑制剂抵抗和ErbB信号通路等信号通路作用于主要靶点，包括EGFR、雌激素受体1（ESR1）和原癌基因酪氨酸蛋白激酶（SRC）。山慈菇可能通过抑制细胞增殖和迁移对治疗NSCLC有益。分子对接显示，活性化合物β-谷甾醇、豆甾醇和2-甲氧基-9,10-二氢菲-4,5-二醇与核心靶基因（EGFR、SRC和ESR1）具有良好的亲和力。核心靶点包括EGFR、SRC、ESR1、表皮生长因子受体2（ERBB2）、雷帕霉素靶蛋白（MTOR）、髓细胞白血病-1（MCL1）、基质金属蛋白酶2（MMP2）、MMP9、血管内皮生长因子受体2（KDR）和Janus激酶2（JAK2）。关键的KEGG通路包括内分泌抵抗、EGFR酪氨酸激酶抑制剂抵抗、ErbB信号传导、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号传导和Rap1信号传导通路。这些核心靶点和通路对NSCLC细胞的增殖具有抑制作用。山慈菇可通过多靶点、多途径分子机制治疗NSCLC，并有效改善NSCLC的预后。本研究可为山慈菇在NSCLC治疗中更广泛应用的进一步机制研究提供参考。
