抗精神病药物氯化锂和抗白血病药物甲磺酸伊马替尼在体外胶质母细胞瘤治疗过程中的拮抗活性。

Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro.

作者信息

Aras Yavuz, Erguven Mine, Aktas Esin, Yazihan Nuray, Bilir Ayhan

机构信息

a İstanbul Faculty of Medicine, Departmentof Neurosurgery , İstanbul University , İstanbul , Turkey.

b Faculty of Engineering and Vocational School of Health Sciences , İstanbul Aydın University , İstanbul , Turkey.

出版信息

Neurol Res. 2016 Sep;38(9):766-74. doi: 10.1080/01616412.2016.1203096. Epub 2016 Jul 1.

DOI:10.1080/01616412.2016.1203096

PMID:27367429

Abstract

OBJECTIVES

Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro.

METHODS

Monolayer and spheroid cultures of the T98G human GBM cell line were treated with an IM and LiCl combination for 72 h. The cell proliferation index, apoptotic index, cell cycle distribution, apoptotic and anti-apoptotic protein levels, and cAMP level as well as the cellular morphology and ultrastructure were evaluated.

RESULTS

All applications inhibited cell proliferation and induced apoptosis. The most substantial decreases in cell proliferation and the caspase-3, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor-alpha (PDGFR-α), multidrug resistance protein-1 (MRP-1), aquaporin-4 (AQP-4) and cAMP levels were induced by the LiCl treatment, which exhibited more pronounced effects compared with the combination treatment. LiCl was less effective in decreasing the MK and B cell lymphoma-2 (Bcl-2) levels compared with the combination treatment. The most substantial decrease in the p170 levels was identified following the combination treatment, whereas IM induced the second greatest decrease. LiCl alone had no effect on the p170 levels. IM induced the most substantial decrease in the phospho-glycogen synthase kinase 3-beta (p-GSK-3β)/glycogen synthase kinase 3-beta (GSK-3β) ratio, and LiCl induced the second most substantial decrease. Both LiCl and the combination treatment induced G2 + M arrest, whereas IM induced G0 + G1 arrest after 72 h of exposure. An apoptotic appearance and autophagic vacuoles were commonly identified in the LiCl, combination and IM groups, respectively.

CONCLUSIONS

The combination of IM and LiCl exhibited an antagonist effect, and MK had a role at this antagonism.

摘要

目的

胶质母细胞瘤（GBM）是中枢神经系统最常见的原发性肿瘤，具有高度恶性和预后不良的特点。本研究旨在探讨甲磺酸伊马替尼（IM）与氯化锂（LiCl）联合应用在治疗中是否具有协同作用，并确定中期因子（MK）在体外是否会影响该治疗效果。

方法

用IM和LiCl联合处理人GBM细胞系T98G的单层培养物和球体培养物72小时。评估细胞增殖指数、凋亡指数、细胞周期分布、凋亡和抗凋亡蛋白水平、cAMP水平以及细胞形态和超微结构。

结果

所有处理均抑制细胞增殖并诱导凋亡。LiCl处理诱导细胞增殖以及半胱天冬酶-3、表皮生长因子受体（EGFR）、血小板衍生生长因子受体-α（PDGFR-α）、多药耐药蛋白-1（MRP-1）、水通道蛋白-4（AQP-4）和cAMP水平最显著下降，与联合处理相比，其作用更明显。与联合处理相比，LiCl在降低MK和B细胞淋巴瘤-2（Bcl-2）水平方面效果较差。联合处理后p170水平下降最为显著，而IM诱导的下降幅度次之。单独使用LiCl对p170水平无影响。IM诱导磷酸化糖原合酶激酶3-β（p-GSK-3β）/糖原合酶激酶3-β（GSK-3β）比值下降最为显著，LiCl诱导的下降幅度次之。LiCl和联合处理均诱导G2 + M期阻滞，而IM在暴露72小时后诱导G0 + G1期阻滞。在LiCl组、联合处理组和IM组中分别常见凋亡外观和自噬空泡。