Li Zesheng, Wang Bo, Wu Jianjian, Han Lei
Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China.
Department of Environment, College of Environment and Resources, Xiangtan University, Xiangtan, China.
Front Pharmacol. 2023 May 30;14:1156492. doi: 10.3389/fphar.2023.1156492. eCollection 2023.
Tricyclic antidepressant is an old and well-established therapeutic agent with a good safety profile, making them an excellent candidate for repurposing. In light of the growing understanding of the importance of nerves in the development and progression of cancer, attention is now being turned to using nerve-targeting drugs for the treatment of cancer, particularly TCAs. However, the specific mechanism by which antidepressants affect the tumor microenvironment of glioblastoma (GBM) is still unclear. Here, we combined bulk RNA sequencing, network pharmacology, single-cell sequencing, molecular docking and molecular dynamics simulation to explore the potential molecular mechanism of imipramine in the treatment of GBM. We first revealed that the imipramine treatment is presumed to target EGFRvIII and neuronal-derived EGFR, which may play a pivotal role in treating GBM by reducing the GABAergic synapse and vesicle-mediated release and other processes thereby modulating immune function. The novel pharmacological mechanisms might provide further research directions.
三环类抗抑郁药是一种古老且成熟的治疗药物，具有良好的安全性，使其成为重新利用的理想候选药物。鉴于人们越来越认识到神经在癌症发生和发展中的重要性，目前正将注意力转向使用神经靶向药物治疗癌症，尤其是三环类抗抑郁药。然而，抗抑郁药影响胶质母细胞瘤（GBM）肿瘤微环境的具体机制仍不清楚。在此，我们结合批量RNA测序、网络药理学、单细胞测序、分子对接和分子动力学模拟，探索丙咪嗪治疗GBM的潜在分子机制。我们首先发现，丙咪嗪治疗可能靶向EGFRvIII和神经元衍生的EGFR，这可能通过减少GABA能突触和囊泡介导的释放等过程来调节免疫功能，从而在治疗GBM中发挥关键作用。这些新的药理机制可能为进一步的研究提供方向。
