Doramectin inhibits glioblastoma cell survival via regulation of autophagy in vitro and in vivo
Doramectin inhibits glioblastoma cell survival via regulation of autophagy in vitro and in vivo
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DOI：
10.3892/ijo.2022.5319
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发表时间：
2022-03-01
影响因子：
5.2
通讯作者：
Gao, Aili
中科院分区：
文献类型：
--
作者：
Chen, Chen;Liang, Hongsheng;Gao, Aili
胶质母细胞瘤（GBM）是最广泛和致命的癌症类型之一。然而，目前没有药物或治疗策略可以完全治愈GBM。多拉菌素（DRM）对体内寄生虫和体外寄生虫具有广泛的活性，广泛用于家畜。在本研究中，DRM对诱导U87和C6 GBM和胶质瘤细胞系中的自噬的影响，以及自噬的机制，进行了检查。首先，透射电镜、质粒转染和western blot分析证实DRM在体外可诱导U87和C6细胞自噬。接下来，MTT和集落形成测定显示DRM诱导的自噬阻止U87和C6细胞活力和集落形成率。此外，DAPI分析和流式细胞术表明，DRM诱导的自噬促进U87和C6细胞凋亡。此外，转录组分析表明，DRM调制的一些基因和途径参与自噬。在裸鼠移植瘤模型中，免疫组织化学染色和TUNEL检测表明DRM对肿瘤的作用与体内一致。这些数据表明DRM主要通过阻断PI3K/AKT/mTOR信号通路诱导GBM细胞自噬。DRM诱导的自噬促进了GBM细胞增殖抑制和凋亡。本研究表明，DRM可能是治疗GBM的有效药物。
Glioblastoma (GBM) is one of the most widespread and lethal types of cancer. However, there are currently no drugs or therapeutic strategies that can completely cure GBM. Doramectin (DRM) has a broad range of activities against endoparasites and ectoparasites, and is extensively used in livestock. In the present study, the effect of DRM on the induction of autophagy in U87 and C6 GBM and glioma cell lines, as well as the mechanism of autophagy, were examined. First, transmission electron microscopy, plasmid transfection and western blot analysis demonstrated that DRM could induce autophagy in U87 and C6 cells in vitro. Next, MTT and colony formation assays revealed that DRM-induced autophagy prevented U87 and C6 cell viability and colony formation ratio. In addition, DRM-induced autophagy promoted U87 and C6 cell apoptosis, as indicated by DAPI analysis and flow cytometry. Furthermore, transcriptome analysis demonstrated that DRM modulated a number of genes and pathways involved in autophagy. In a nude mouse xenograft model, immunohistochemical staining and the TUNEL assay demonstrated that the effect of DRM on the tumor was consistent with that in vivo. These data indicated that DRM induced autophagy mainly by blocking the PI3K/AKT/mTOR signaling pathway in GBM cells. DRM-induced autophagy promoted the inhibition of GBM cell proliferation and apoptosis in vitro and in vivo. The present study suggested that DRM may be an effective drug for the treatment of GBM.