Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool.
Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool.
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DOI：
10.1038/cddiscovery.2017.30
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发表时间：
2017
影响因子：
7
通讯作者：
Wrosch JK
中科院分区：
文献类型：
--
作者：
Dahlmanns M;Yakubov E;Chen D;Sehm T;Rauh M;Savaskan N;Wrosch JK
在寻找新的潜在化疗药物时，化合物对健康细胞的毒性是一个重要因素。脑及其功能单位神经元在脑肿瘤的放射和化学治疗期间尤其受到威胁。潜在化合物不仅对神经元存活而且对神经元功能的影响需要考虑。因此，在这项研究中，我们的目的是了解化学治疗xCT抑制对健康神经元细胞的生物学效应与我们的突触光遗传学功能分析工具（SOFA）。我们结合常用的方法，如形态学标记，神经元功能和细胞代谢的调查。谷氨酸-胱氨酸交换体xCT（SLC 7A 11，系统XC−）是恶性脑肿瘤中的主要谷氨酸输出体，因此是治疗致命性胶质母细胞瘤（WHO III级和IV级）的相关药物靶点。最近，已经发现两种称为索拉非尼（Nexavar）和erastin的小分子可以有效地阻断xCT功能。我们研究了用临床相关浓度的索拉非尼和erastin处理的原代海马培养物（含有神经元和神经胶质细胞）的神经元形态、代谢分泌组特征、突触功能和细胞代谢。我们发现索拉非尼在治疗24小时后已经严重损害了神经元。值得注意的是，同样在较低浓度下，没有监测到形态学损伤或代谢紊乱，索拉非尼仍然干扰突触和代谢稳态。与此相反，erastin处理的神经元大多表现出不明显的形态和代谢率。然而，适当的神经元功能的关键参数，如突触囊泡池的大小，被破坏后erastin应用。总之，我们的数据显示，虽然索拉非尼和erastin有效地抑制xCT功能，但它们也干扰了基本的神经元（突触）功能。这些发现强调了研究潜在的神经肿瘤和一般癌症化疗药物对健康神经元细胞及其功能的影响的特别重要性，如SOFA工具所揭示的。
In the search for new potential chemotherapeutics, the compounds’ toxicity to healthy cells is an important factor. The brain with its functional units, the neurons, is especially endangered during the radio- and chemotherapeutic treatment of brain tumors. The effect of the potential compounds not only on neuronal survival but also neuronal function needs to be taken into account. Therefore, in this study we aimed to comprehend the biological effects of chemotherapeutic xCT inhibition on healthy neuronal cells with our synaptic optogenetic function analysis tool (SOFA). We combined common approaches, such as investigation of morphological markers, neuronal function and cell metabolism. The glutamate-cystine exchanger xCT (SLC7A11, system Xc−) is the main glutamate exporter in malignant brain tumors and as such a relevant drug target for treating deadly glioblastomas (WHO grades III and IV). Recently, two small molecules termed sorafenib (Nexavar) and erastin have been found to efficiently block xCT function. We investigated neuronal morphology, metabolic secretome profiles, synaptic function and cell metabolism of primary hippocampal cultures (containing neurons and glial cells) treated with sorafenib and erastin in clinically relevant concentrations. We found that sorafenib severely damaged neurons already after 24 h of treatment. Noteworthy, also at a lower concentration, where no morphological damage or metabolic disturbance was monitored, sorafenib still interfered with synaptic and metabolic homeostasis. In contrast, erastin-treated neurons displayed mostly inconspicuous morphology and metabolic rates. Key parameters of proper neuronal function, such as synaptic vesicle pool sizes, were however disrupted following erastin application. In conclusion, our data revealed that while sorafenib and erastin effectively inhibited xCT function they also interfered with essential neuronal (synaptic) function. These findings highlight the particular importance of investigating the effects of potential neurooncological and general cancer chemotherapeutics also on healthy neuronal cells and their function as revealed by the SOFA tool.
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