Intensive Care Unit-Laishan, The Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China.
Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China.
Neoplasma. 2024 Aug;71(4):333-346. doi: 10.4149/neo_2024_230909N479.
Given the infiltrative nature of human glioblastoma (GBM), cocktail drug therapy will remain a vital tool for the treatment of the disease. We investigated fluspirilene, perphenazine, and sulpiride, three classic anti-schizophrenic drugs, as possible anti-GBM agents. The CCK-8 assay demonstrated that fluspirilene possesses the most outstanding anti-GBM effect. We performed molecular mechanisms studies in vitro and an orthotopic xenograft model in mice. Fluspirilene inhibited proliferation and migration in vitro in U87MG and U251 GBM cell lines. Flow cytometry demonstrated that treatment increased apoptosis and cells accumulated in the G2/M phase. Our analysis of publicly available expression data for several cell lines treated with the drug led to the identification of several genes, including KIF20A, that are downregulated by fluspirilene and lead to growth inhibition/apoptosis. We also demonstrated that siRNA knockdown of KIF20A, a member of the kinesin family, attenuated cell proliferation in GBM cells and an orthotopic xenograft model in mice. A regulator of KIF20A, the oncogenic transcription factor FOXM1, was identified using the String database, which harbors protein interaction networks. In fluspirilene-treated cells, FOXM1 protein was decreased, indicating that KIF20A was downregulated in the presence of the drug due to decreased FOXM1 protein. These results demonstrate that fluspirilene is an effective anti-GBM agent that works by suppressing the FOXM1-KIF20A oncogenic axis.
鉴于人类胶质母细胞瘤 (GBM) 的浸润特性，鸡尾酒药物疗法仍将是治疗这种疾病的重要工具。我们研究了氟哌啶醇、奋乃静和舒必利这三种经典的抗精神分裂症药物，作为可能的抗 GBM 药物。CCK-8 测定表明氟哌啶醇具有最突出的抗 GBM 作用。我们在体外和小鼠原位异种移植模型中进行了分子机制研究。氟哌啶醇在 U87MG 和 U251 GBM 细胞系中抑制体外增殖和迁移。流式细胞术表明，该药物处理后细胞凋亡增加，细胞积累在 G2/M 期。我们对几种用药物处理的细胞系的公开表达数据进行了分析，确定了几个基因，包括 KIF20A，该基因被氟哌啶醇下调，导致生长抑制/凋亡。我们还证明，KIF20A（驱动蛋白家族的成员）的 siRNA 敲低可减弱 GBM 细胞的增殖和小鼠的原位异种移植模型。FOXM1 是 KIF20A 的调节因子，通过 String 数据库鉴定，该数据库包含蛋白质相互作用网络。在氟哌啶醇处理的细胞中，FOXM1 蛋白减少，表明在存在药物的情况下 KIF20A 下调，因为 FOXM1 蛋白减少。这些结果表明氟哌啶醇是一种有效的抗 GBM 药物，通过抑制 FOXM1-KIF20A 致癌轴起作用。
