Zhuo Chuanjun, Li Chao, Zhang Qiuyu, Yang Lei, Zhang Ying, Chen Ximing, Ma Xiaoyan, Li Ranli, Wang Lina, Tian Hongjun
Computational Biology and Computational Psychiatry Center (CBCP), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China.
Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PGNP_Lab), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China.
Int J Neuropsychopharmacol. 2025 Jun 6;28(6). doi: 10.1093/ijnp/pyaf029.
Vortioxetine is a serotonin reuptake inhibitor and serotonin receptor modulator used for the treatment of major depressive disorder, but recent studies have also reported anticancer effects in models of glioblastoma. Given the well-established benefits of drug repositioning, we examined the pharmacological mechanism for these anticancer actions using bioinformatics and molecular docking.
Putative molecular targets for vortioxetine were identified by searching DrugBank, GeneCards, SwissTargetPrediction, Comparative Toxicogenomics Database, and SuperPred databases, while glioblastoma-related proteins were identified using GeneCards, Online Mendelian Inheritance in Man; , and Therapeutic Target Database . A protein-protein interaction (PPI) network was constructed from vortioxetine targets also involved in glioblastoma to identify core (hub) targets, which were then characterized by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using database for annotation, visualization, and integrated discovery. Cytoscape was utilized to generate a drug-pathway-target-disease network, and molecular docking simulations were performed to evaluate direct interactions between vortioxetine and core target proteins.
A total of 234 unique vortioxetine protein targets were identified. Among 234 vortioxetine targets identified, 48 were also related to glioblastoma. Topological analysis of the PPI network revealed 5 core targets: the serine/threonine kinase AKT1, transcription factor hypoxia-inducible factor (HIF)-1, cell adhesion molecule cadherin-E, NF-κB subunit p105, and prostaglandin-endoperoxide synthase 2. According to GO and KEGG pathway analyses, the anticancer efficacy of vortioxetine may be mediated by effects on glucose metabolism, cell migration, phosphorylation, inflammatory responses, apoptosis, and signaling via Rap1, chemical carcinogenesis-reactive oxygen species, and HIF-1. Molecular docking revealed moderately strong affinities between vortioxetine and 4 core targets.
This study suggests that vortioxetine may inhibit glioblastoma development through direct effects on multiple targets and further emphasizes the value of bioinformatics analyses for drug repositioning.
伏硫西汀是一种用于治疗重度抑郁症的5-羟色胺再摄取抑制剂和5-羟色胺受体调节剂，但最近的研究也报道了其在胶质母细胞瘤模型中的抗癌作用。鉴于药物重新定位已被充分证实的益处，我们使用生物信息学和分子对接技术研究了这些抗癌作用的药理学机制。
通过搜索药物银行、基因卡、瑞士靶点预测、比较毒理基因组学数据库和超级预测数据库来确定伏硫西汀的推定分子靶点，同时使用基因卡、人类在线孟德尔遗传和治疗靶点数据库来确定胶质母细胞瘤相关蛋白。从也参与胶质母细胞瘤的伏硫西汀靶点构建蛋白质-蛋白质相互作用（PPI）网络，以识别核心（枢纽）靶点，然后使用注释、可视化和综合发现数据库通过基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析对其进行表征。利用Cytoscape生成药物-通路-靶点-疾病网络，并进行分子对接模拟以评估伏硫西汀与核心靶点蛋白之间的直接相互作用。
共鉴定出234个独特的伏硫西汀蛋白靶点。在鉴定出的234个伏硫西汀靶点中，48个也与胶质母细胞瘤相关。PPI网络的拓扑分析揭示了5个核心靶点：丝氨酸/苏氨酸激酶AKT1、转录因子缺氧诱导因子（HIF）-1、细胞粘附分子钙粘蛋白-E、NF-κB亚基p105和前列腺素内过氧化物合酶2。根据GO和KEGG通路分析，伏硫西汀的抗癌功效可能通过对葡萄糖代谢、细胞迁移、磷酸化、炎症反应、细胞凋亡以及通过Rap1、化学致癌-活性氧和HIF-1的信号传导的影响来介导。分子对接显示伏硫西汀与4个核心靶点之间具有中等强度的亲和力。
本研究表明伏硫西汀可能通过对多个靶点的直接作用来抑制胶质母细胞瘤的发展，并进一步强调了生物信息学分析在药物重新定位中的价值。
