A Mechanistic Study of the Feasibility of Ursodeoxycholic Acid in the Treatment of Colon Adenocarcinoma.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-03-12 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S500721

Shuyu Liu, Mengyue Zhou, Xiaoli Huang, Peng Chen, Quanpeng Li, Yuting Wang, Xianxiu Ge, Fei Wang, Jianing Xu, Jiayi Gu, Lin Miao, Xueting Deng

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引用次数: 0

Abstract

Purpose: Bile acids promote the progression of colon adenocarcinoma (COAD), and ursodeoxycholic acid (UDCA) is a key drug in promoting bile acid excretion, but its role in COAD unclear. Our study aims to investigate the relationship between COAD and bile acid metabolism and to assess the feasibility of UDCA for the treatment of COAD.

Methods: Firstly, biological targets closely related to COAD were identified: Based on the cancer genome atlas (TCGA) database, the core genes of COAD were obtained by differential expression analysis and weighted gene-coexpression network analysis (WGCNA), and subjected to gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Secondly, finding a drug by target, after identifying UDCA as a candidate drug, the feasibility of UDCA in treating COAD was verified in reverse: Using databases to collect potential targets for COAD and UDCA, and the intersecting genes were the potential targets for UDCA to exert anti-tumor effects. Then Autodock was used for molecular docking to analyze the interaction between UDCA and core target proteins. Finally, experimental validation was performed: MTT assay, wound healing, transwell migration, and angiogenesis assays were used to detect the effects of UDCA on cell proliferation, migration, invasion, and neovascularization.

Results: 2064 differential genes were screened from TCGA. WGCNA obtained the module most relevant to CRC, containing 493 genes. KEGG analysis found that overlapping genes were mainly concentrated in bile acid metabolic pathways. A total of 26 UDCA anti-tumor targets were obtained in database, and 5 core targets were selected by STRING database and Cytoscape software: TNF, CYP27B1, MDM2, MMP2, CASP3. Molecular docking results showed that UDCA had good binding activity with the core targets. In vitro experiment showed UDCA effectively inhibited the proliferation, migration, invasion and neovascularization in colon cancer cells.

Conclusion: The antitumor activity of ursodeoxycholic acid may be related to cell apoptosis, proliferation, migration and vascular neogenesis.

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熊去氧胆酸治疗结肠腺癌可行性的机制研究。

目的：胆汁酸促进结肠癌（COAD）的进展，熊去氧胆酸（UDCA）是促进胆汁酸排泄的关键药物，但其在COAD中的作用尚不清楚。我们的研究旨在探讨COAD与胆汁酸代谢的关系，并评估UDCA治疗COAD的可行性。方法：首先，确定与COAD密切相关的生物学靶点：基于癌症基因组图谱（TCGA）数据库，通过差异表达分析和加权基因共表达网络分析（WGCNA）获得COAD的核心基因，并进行基因本体（GO）功能注释和京都基因基因组百科全书（KEGG）途径富集分析。其次，通过靶点寻找药物，在确定UDCA为候选药物后，反向验证UDCA治疗COAD的可行性：利用数据库收集COAD和UDCA的潜在靶点，交叉基因为UDCA发挥抗肿瘤作用的潜在靶点。然后利用Autodock进行分子对接，分析UDCA与核心靶蛋白的相互作用。最后进行实验验证：采用MTT法、伤口愈合法、跨井迁移法和血管生成法检测UDCA对细胞增殖、迁移、侵袭和新生血管的影响。结果：从TCGA中筛选到2064个差异基因。WGCNA获得了与CRC最相关的模块，包含493个基因。KEGG分析发现重叠基因主要集中在胆汁酸代谢途径。在数据库中共获得26个UDCA抗肿瘤靶点，通过STRING数据库和Cytoscape软件筛选出5个核心靶点：TNF、CYP27B1、MDM2、MMP2、CASP3。分子对接结果表明，UDCA与核心靶点具有良好的结合活性。体外实验表明，UDCA能有效抑制结肠癌细胞的增殖、迁移、侵袭和新生血管形成。结论：熊去氧胆酸的抗肿瘤活性可能与细胞凋亡、增殖、迁移和血管新生有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.