Screening of anti-glioma effects induced by sigma-1 receptor ligands: Potential new use for old anti-psychiatric medicines
Screening of anti-glioma effects induced by sigma-1 receptor ligands: Potential new use for old anti-psychiatric medicines
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DOI：
10.1016/j.ejca.2009.07.011
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发表时间：
2009-11-01
影响因子：
8.4
通讯作者：
Kiss, Robert
中科院分区：
文献类型：
--
作者：
Megalizzi, Veronique;Decaestecker, Christine;Kiss, Robert
胶质母细胞瘤(GBM)的预后仍然较差。在确诊时，原发肿块中的迁移细胞已经发生了对远处脑组织的弥漫性侵犯。选择性Sigma-1激动剂4-(N-苄基哌啶-4-基)-4-碘苯甲酰胺(4-IBP)在胶质母细胞瘤中的抗癌作用已有报道，因此本工作研究了17种Sigma-1受体激动剂或拮抗剂对胶质母细胞瘤细胞的作用，包括目前上市的药物氟伏沙明、右美沙芬、多奈哌齐、美金胺和氟哌啶醇。我们首先证明了已建立的GBM细胞系、原代培养细胞和手术标本都表达Sigma-1受体。然后，通过定量视频显微镜分析，体外分析了抗增殖和抗迁移对人胶质母细胞瘤细胞系的影响。这些细胞监测分析揭示了对有丝分裂细胞过程的特定影响。使用原位移植到免疫受损小鼠脑内的侵袭性胶质瘤模型，我们表明，与替莫唑胺或多奈哌齐单独使用相比，多奈哌齐和替莫唑胺联合使用在延长生存期方面具有额外的好处。如果进一步的多奈哌齐与替莫唑胺的啮齿动物剂量范围研究继续显示在该模型中有益处的证据，临床研究正在计划中。(C)2009爱思唯尔有限公司。保留所有权利，
The prognosis of glioblastoma (GBM) remains poor. Diffuse invasion of distant brain tissue by migrating cells from the primary tumour mass has already occurred at time of diagnosis. Anti-cancer effects of a selective sigma-1 agonist, 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), in glioblastoma were shown previously, leading to the present work where the effects on glioblastoma cells of 17 agonists or antagonists of sigma-1 receptors were studied, including currently marketed drugs fluvoxamine, dextromethorphan, donepezil, memantine and haloperidol. We first showed that established GBM cell lines, primary cultures and surgical specimens express sigma-1 receptors. In vitro analyses then focused on anti-proliferation and anti-migratory effects on human glioblastoma cell lines using quantitative videomicroscopy analyses. These cell monitoring assays revealed specific impacts on the mitotic cell process. Using an aggressive glioma model orthotopically grafted into the brains of immunocompromised mice, we showed that combining donepezil and temozolomide gave additive benefit in terms of long survivors as compared to temozolomide or donepezil alone. Clinical study is planned if further rodent dose-ranging studies of donepezil with temozolomide continue to show evidence of benefit in this model. (C) 2009 Elsevier Ltd. All rights reserved,