通过细胞实验和网络药理学探索瑞香素对急性髓系白血病的作用机制。

Exploring the mechanism of fraxetin against acute myeloid leukemia through cell experiments and network pharmacology.

机构信息

Department of Pediatrics (Children Hematological Oncology), Children Hematological Oncology and Birth Defects Laboratory, Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.

出版信息

BMC Complement Med Ther. 2024 Jun 10;24(1):226. doi: 10.1186/s12906-024-04529-8.

DOI:10.1186/s12906-024-04529-8

PMID:38858650

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11163689/

Abstract

OBJECTIVE

Previous studies have shown that fraxetin has antitumor activity in a variety of tumors, but its role in acute myeloid leukemia (AML) remains unclear. In this study, we aimed to evaluate the anti-AML effect of fraxetin through cell experiments and network pharmacology analysis.

METHODS

The inhibitory and apoptotic effects of fraxetin on AML cells were determined by CCK-8 and flow cytometry experiments. Potential targets of fraxetin and AML-related targets were screened using public databases. PPI network, GO functional enrichment and KEGG pathway enrichment analyses were performed to predict the hub targets and signaling pathways by which fraxetin alleviates AML. Molecular docking was used to determine the fraxetin binding sites on hub targets. Using the GEPIA database, the expression of hub targets was analyzed in relation to the overall survival of AML patients.

RESULTS

Cell experiments showed that fraxetin inhibits AML cell proliferation and induces apoptosis. To explore the potential mechanism of fraxetin, 29 shared targets of fraxetin and AML were obtained through screening online public databases. Among them, AKT1, TNF, SRC, etc., are related to AML cell apoptosis. The expression levels of SRC, NOS3, VAV1, LYN, and PTGS1 were associated with the overall survival of AML patients (p value < 0.05). The enrichment analysis results identified the main pathways, namely, focal adhesion and the PI3K-AKT signaling pathway, that affected the proliferation and apoptosis of AML cells. The analysis of hub targets of the PPI network showed that AKT1, TNF, CTNNB1, etc., were hub targets, which were related to the proliferation and apoptosis of AML cells. The results of molecular docking showed that the hub targets had good binding with fraxetin.

CONCLUSION

Fraxetin may inhibit AML cell proliferation and induce AML cell apoptosis through multiple targets, such as AKT1, SRC, and EGFR, and multiple pathways, such as focal adhesion and the PI3K-AKT signaling pathway.

摘要

目的

先前的研究表明，秦皮素在多种肿瘤中具有抗肿瘤活性，但它在急性髓系白血病（AML）中的作用尚不清楚。本研究旨在通过细胞实验和网络药理学分析评估秦皮素对 AML 的抗作用。

方法

通过 CCK-8 和流式细胞术实验确定秦皮素对 AML 细胞的抑制和凋亡作用。使用公共数据库筛选秦皮素的潜在靶点和与 AML 相关的靶点。通过 PPI 网络、GO 功能富集和 KEGG 途径富集分析，预测秦皮素缓解 AML 的关键靶点和信号通路。使用分子对接确定秦皮素在关键靶点上的结合位点。通过 GEPIA 数据库分析关键靶点的表达与 AML 患者总生存率的关系。

结果

细胞实验表明，秦皮素抑制 AML 细胞增殖并诱导细胞凋亡。为了探索秦皮素的潜在机制，通过在线筛选公共数据库获得了 29 个秦皮素和 AML 的共有靶点。其中，AKT1、TNF、SRC 等与 AML 细胞凋亡有关。SRC、NOS3、VAV1、LYN 和 PTGS1 的表达水平与 AML 患者的总生存率相关（p 值<0.05）。富集分析结果确定了主要途径，即粘着斑和 PI3K-AKT 信号通路，这些途径影响 AML 细胞的增殖和凋亡。PPI 网络的关键靶点分析表明，AKT1、TNF、CTNNB1 等是关键靶点，与 AML 细胞的增殖和凋亡有关。分子对接结果表明，关键靶点与秦皮素具有良好的结合能力。