Drug Design, Development and Therapy (Mar 2025)
A Mechanistic Study of the Feasibility of Ursodeoxycholic Acid in the Treatment of Colon Adenocarcinoma
Abstract
Shuyu Liu,1,2,* Mengyue Zhou,3,* Xiaoli Huang,2,* Peng Chen,2 Quanpeng Li,1 Yuting Wang,1 Xianxiu Ge,1 Fei Wang,1 Jianing Xu,1 Jiayi Gu,4 Lin Miao,1 Xueting Deng1 1Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Gastroenterology, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, People’s Republic of China; 4Department of Neurology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin Miao; Xueting Deng, Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan, Nanjing, Jiangsu, 210011, People’s Republic of China, Tel +86-13913862526, Email [email protected]; [email protected]: 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.Keywords: ursodeoxycholic acid, colon adenocarcinoma treatment, bile acid metabolism, cell death
