Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
Department of Rehabilitation Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China.
BMC Complement Med Ther. 2024 Jun 5;24(1):214. doi: 10.1186/s12906-024-04516-z.
Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer.
The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed.
We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A's interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels.
This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A.
传统中药（TCM）在肿瘤治疗中得到了广泛的应用，产生了有前途的治疗候选药物。先前的研究表明，从 Centipeda minima（L.）A.Br.（C.minima）这种 TCM 草药中提取的天然倍半萜内酯 Brevilin A 具有抗癌特性，特别是针对肺癌。然而，其作用的潜在机制仍不清楚。本研究采用网络药理学和实验分析方法，揭示 Brevilin A 治疗肺癌的分子机制。
利用 Batman-TCM、Swiss Target Prediction、Pharmmapper、SuperPred 和 BindingDB 数据库筛选出 Brevilin A 的靶点。从 GEO、Genecards、OMIM、TTD 和 Drugbank 数据库中获取与肺癌相关的靶点。利用 Cytoscape 软件构建蛋白质-蛋白质相互作用（PPI）网络。使用 R 软件进行基因本体论（GO）、京都基因与基因组百科全书（KEGG）、基因集富集分析（GSEA）和基因-通路相关性分析。为了验证网络药理学结果，进行了分子对接、分子动力学模拟和体外实验。
我们鉴定出 599 个与 Brevilin A 相关的靶点和 3864 个与肺癌相关的靶点，其中 155 个重叠基因被认为是 Brevilin A 治疗肺癌的候选靶点。PPI 网络突出了 STAT3、TNF、HIF1A、PTEN、ESR1 和 MTOR 作为潜在的治疗靶点。GO 和 KEGG 分析显示，有 2893 个 GO 术语和 157 个 KEGG 途径被富集，包括 PI3K-Akt 信号通路、FoxO 信号通路和 HIF-1 信号通路。GSEA 表明枢纽基因与肺癌密切相关。基因-通路相关性分析表明，枢纽基因与细胞对缺氧途径的反应存在显著关联。分子对接和动力学模拟证实了 Brevilin A 分别与 PTEN 和 HIF1A 的相互作用。体外实验表明，Brevilin A 诱导 A549 细胞呈剂量和时间依赖性死亡。值得注意的是，Brevilin A 处理显著降低了 HIF-1α mRNA 的表达，同时增加了 PTEN mRNA 的水平。
本研究表明，Brevilin A 通过多靶点、多通路方式发挥抗癌作用，可能涉及 HIF 通路。这些结果为 Brevilin A 的临床应用提供了理论基础。
