School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; Shaanxi Key Laboratory of "Qiyao" Resources and Anti-tumor Acitivities/Shanxi Plant Extract Engineering Technology Research Center, Xi'an, 710061, China.
Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
Comput Biol Chem. 2021 Oct;94:107396. doi: 10.1016/j.compbiolchem.2020.107396. Epub 2020 Oct 1.
SUANPANQI, the pseudo phosphorous stem of Cremastra appendiculata, is one of the most well-known traditional Chinese medicine, which has been shown to inhibit tumorigenesis in various human cancers. However, the underlying mechanism of SUANPANQI treatment against breast cancer (BRCA) remains unclear. In this study. we aim to investigate the bioactive compounds and mechanisms of SUANPANQI in the treatment of BRCA based on network pharmacology and molecular docking.
The compounds were collected from previous research. SwissADME was used to screen bioactive compounds. The targets corresponding to SUANPANQI and BRCA were obtained using MalaCards and SwissTargetPrediction. SUANPANQI-related and BRCA-related targets were found and then overlapped to get intersections, which represented potential anti-BRCA targets of SUANPANQI. The Cytoscape software was used to construct bioactive compounds targeting the BRCA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the targets was extracted from the metascape database, then conducted using the Cluster Profiler package in R software. Protein-Protein interaction (PPI) network was constructed using the STRING online database and analyzed using Cytoscape software. Pivotal genes were screened using the topological analysis, survival analysis, and pathological stage analysis. Molecular docking analysis was used to verify whether the bioactive compounds had a definite affinity with the pivotal targets.
Sixty-five bioactive compounds of SUANPANQI were involved with 225 predicted BRCA targets. Then, a compound-target network and a PPI network were constructed. The GO analysis and KEGG enrichment analysis suggested that SUANPANQI worked against BRCA via PI3K-Akt, Ras, FoxO, Rap1, and ErbB signaling pathways, etc. After topological analysis, survival analysis, and pathological stage analysis of the SUANPANQI potential targets against BRCA, 6 pivotal target genes (AR, HSP90AA1, MMP9, PGR, PTGS2, TNF) that were highly responsible for the therapeutic effects of SUANPANQI against BRCA were obtained. Molecular docking results showed that 6 bioactive compounds of SUANPANQI had strong binding efficiency with the 6 pivotal genes.
The present study clarifies the mechanism of SUANPANQI against BRCA through multiple targets and pathways, and provides evidence to support its clinical use.
山萮菜，是密苞曲环兰的假磷茎，是最著名的中药之一，已被证明能抑制多种人类癌症的癌变。然而，山萮菜治疗乳腺癌（BRCA）的潜在机制尚不清楚。在这项研究中，我们旨在基于网络药理学和分子对接技术，研究山萮菜治疗 BRCA 的生物活性化合物和机制。
化合物从前人的研究中收集。SwissADME 用于筛选生物活性化合物。使用 MalaCards 和 SwissTargetPrediction 获得与山萮菜和 BRCA 对应的靶点。找到山萮菜相关和 BRCA 相关的靶点，然后重叠以获得交集，这代表了山萮菜治疗 BRCA 的潜在靶点。使用 Cytoscape 软件构建针对 BRCA 网络的生物活性化合物靶标。从 metascape 数据库中提取靶点的基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，并使用 R 软件中的 Cluster Profiler 包进行分析。使用 STRING 在线数据库构建蛋白质-蛋白质相互作用（PPI）网络，并使用 Cytoscape 软件进行分析。使用拓扑分析、生存分析和病理分期分析筛选关键基因。使用分子对接分析验证生物活性化合物是否与关键靶标具有明确的亲和力。
山萮菜涉及 65 种生物活性化合物，与 225 个预测的 BRCA 靶点相关。然后构建了一个化合物-靶标网络和一个 PPI 网络。GO 分析和 KEGG 富集分析表明，山萮菜通过 PI3K-Akt、Ras、FoxO、Rap1 和 ErbB 信号通路等作用于 BRCA。经过拓扑分析、生存分析和病理分期分析山萮菜对 BRCA 的潜在靶点后，获得了 6 个关键靶基因（AR、HSP90AA1、MMP9、PGR、PTGS2、TNF），这些基因对山萮菜治疗 BRCA 的疗效负有高度责任。分子对接结果表明，山萮菜的 6 种生物活性化合物与 6 个关键基因具有很强的结合效率。
本研究通过多靶点和多途径阐明了山萮菜治疗 BRCA 的机制，为其临床应用提供了证据支持。
