Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells.
Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells.
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DOI：
10.18632/oncotarget.6314
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发表时间：
2016-01-05
期刊：
影响因子：
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通讯作者：
Bar EE
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文献类型：
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作者：
Spina R;Voss DM;Asnaghi L;Sloan A;Bar EE
多形性胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，中位生存期约为1年。这种不良预后主要归因于手术切除后的治疗抗性和肿瘤复发，其根本原因被认为存在于胶质母细胞瘤干细胞（GSC）中。使用胶质细胞酸性蛋白（GFAP）作为星形胶质细胞分化的报告，我们分离出多个克隆从三个独立的GSC线，表达GFAP在一个非常稳定的方式。我们接下来表明GFAP的表达升高与体外克隆形成和体内致瘤性降低相关。利用这种体外基于细胞的分化报告系统，我们筛选了化学文库，并确定了非去极化神经肌肉阻滞剂（NNMB），苯磺酸阿曲库铵，作为一种小分子，有效地诱导星形胶质细胞，但不是神经元分化的GSC。在功能上，苯磺酸阿曲库铵处理显著抑制了几种独立的患者源性GSC神经球系的克隆形成能力，这种现象在很大程度上是不可逆的。第二个NNMB，维库溴铵，也诱导GSC星形胶质细胞分化，而二甲基苯基哌嗪（DMPP），烟碱乙酰胆碱受体（nAChR）激动剂，显着阻断苯磺酸阿曲库铵促分化活性。为了研究nAChR在神经胶质瘤中的临床重要性，我们检查了临床结局，发现肿瘤过表达CHRNA1或CHRNA9（编码AChR-α 1或AChR-α 9）的神经胶质瘤患者的总生存期显著缩短。最后，我们发现用苯磺酸阿曲库铵对表达CHRNA1和CHRNA9的GSC进行离体预处理显著增加了异种移植这些细胞的小鼠的存活率，因此表明肿瘤起始亚群已经减少。
Glioblastoma multiforme (GBM) are the most common primary malignant brain tumor in adults, with a median survival of about one year. This poor prognosis is attributed primarily to therapeutic resistance and tumor recurrence after surgical removal, with the root cause suggested to be found in glioblastoma stem cells (GSCs). Using glial fibrillary acidic protein (GFAP) as a reporter of astrocytic differentiation, we isolated multiple clones from three independent GSC lines which express GFAP in a remarkably stable fashion. We next show that elevated expression of GFAP is associated with reduced clonogenicity in vitro and tumorigenicity in vivo. Utilizing this in vitro cell-based differentiation reporter system we screened chemical libraries and identified the non-depolarizing neuromuscular blocker (NNMB), Atracurium Besylate, as a small molecule which effectively induces astroglial but not neuronal differentiation of GSCs. Functionally, Atracurium Besylate treatment significantly inhibited the clonogenic capacity of several independent patient-derived GSC neurosphere lines, a phenomenon which was largely irreversible. A second NNMB, Vecuronium, also induced GSC astrocytic differentiation while Dimethylphenylpiperazinium (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, significantly blocked Atracurium Besylate pro-differentiation activity. To investigate the clinical importance of nAChRs in gliomas, we examined clinical outcomes and found that glioma patients with tumors overexpressing CHRNA1 or CHRNA9 (encoding for the AChR-α1 or AChR-α9) exhibit significant shorter overall survival. Finally, we found that ex-vivo pre-treatment of GSCs, expressing CHRNA1 and CHRNA9, with Atracurium Besylate significantly increased the survival of mice xenotransplanted with these cells, therefore suggesting that tumor initiating subpopulations have been reduced.