PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, β-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the β-catenin protein expression was also determined by immunocytochemistry. ILO (p < 0.05) and TMZ (p < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment (p < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups (p < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression (p < 0.001). The expressions of β-catenin (p < 0.001), Dvl2 (p < 0.001), Twist (p < 0.001), and Slug (p < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and β-catenin expression and has the potential to be repurposed against GBM.
摘要：
胶质母细胞瘤（GBM）是一种致命的星形胶质细胞瘤，预后差，治疗耐药。重新使用潜在的FDA批准的药物，如抗精神病药，可以及时和具有成本效益的方式解决这些问题。流行病学研究表明，使用抗精神病药的精神分裂症患者的GBM发生率较低。因此,我们的目的是研究非典型抗精神病药物伊洛哌酮(ILO)单药和替莫唑胺(TMZ)联合治疗GBM的治疗潜力.该研究评估了国际劳工组织的生长抑制作用，TMZ,以及使用MTT测定在U-87MG和T-98G细胞系上的它们的组合(ILO+TMZ)。测定药物相互作用系数(CDI),并将具有协同作用的剂量用于后续实验，包括迁徙,入侵,和TUNEL检测。DRD2、β-catenin、Dvl2,Twist,和Slug通过RTq-PCR进行评估，而β-连环蛋白的表达也通过免疫细胞化学测定。ILO(p<0.05)和TMZ(p<0.01)在所有测试剂量下均显著抑制U-87MG细胞的生长。两种药物的60μM的组合显示与CDI<1的协同活性。在联合治疗的情况下，迁移和凋亡的抑制更为明显（p<0.001）。还发现在ILO和组合处理组中对侵入细胞的抑制是显著的(p<0.001)。ILO和联合治疗也显著下调DRD2的表达,而TMZ上调表达(p<0.001)。β-catenin的表达(p<0.001)，Dvl2（p<0.001），Twist(p<0.001)，和Slug(p<0.001)在所有治疗组中与载体对照相比也显著下调。数据表明，国际劳工组织具有很强的生长抑制活性，可能是由于其对DRD2和β-连环蛋白表达的影响，并且有可能针对GBM重新利用。
