文章：

重新利用氯马斯汀靶向胶质母细胞瘤细胞干性

Repurposing Clemastine to Target Glioblastoma Cell Stemness

原文发布日期：18 September 2023

DOI: 10.3390/cancers15184619

类型: Article

开放获取: 是

英文摘要：

Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearingPDGFRAamplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that the Emopamil Binding Protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment.

摘要翻译： 

脑肿瘤起始细胞（BTICs）与肿瘤细胞可塑性共同促进胶质母细胞瘤（GBM）的进展。本研究发现，用于治疗花粉症及过敏症状的非处方药氯马斯汀，能有效减弱携带PDGFRA扩增的原代BTIC培养物的干细胞特性并抑制其增殖。氯马斯汀对BTICs的作用伴随其基因表达谱的改变，提示细胞向更分化状态转变，这与该药物促进正常少突胶质前体细胞（OPCs）分化为成熟少突胶质细胞的作用机制相呼应。通过药物靶点功能实验，我们发现胆固醇生物合成通路中的角鲨烯环氧酶（EBP）对BTICs的增殖至关重要，且是介导氯马斯汀抑制作用的关键靶点。最后，我们证实以神经前体细胞来源、主要呈现前神经元亚型特征的小鼠胶质瘤模型同样对氯马斯汀处理敏感。综上，本研究揭示了维持GBM干细胞特性及前体细胞特征的关键通路，阐明了BTICs对EBP的依赖性，并提示具有促进OPC分化活性的非肿瘤类低毒性药物可通过靶向GBM干细胞特性实现老药新用，为GBM治疗提供新策略。

原文链接：

Repurposing Clemastine to Target Glioblastoma Cell Stemness