瓜陵菜根中分离出的天然化合物瓜陵菜酮能够通过不同机制体现出抗肿瘤活性，在许多种癌症中均有体现。然而，它在治疗预后欠佳的一种名为胶质母细胞瘤（GBM）的肿瘤方面的疗效尚未得到严格的研究。我们使用化合物作用模型来评估其在GBM中的作用。我们使用涂布瓜陵菜酮及CCK-8，集落形成和EdU实验，流式细胞术和跨嗎孔3D腫瘤球遷移和GBM腦器官剖面共同培養遷移實驗来评估增殖，生存，凋亡和侵入/迁移的特性。对瓜陵菜酮处于不同浓度下的处理细胞进行RNA测序分析，以确定瓜陵菜酮在GBM细胞中的抗肿瘤作用的潜在靶基因。对使用涂布瓜陵菜酮的细胞系和从正交异体移植中获得的样本进行了Western blot分析，免疫荧光和免疫组化分析以评估蛋白质水平。使用特异性激活剂识别介导作用的层次。结果表明，瓜陵菜酮明显抑制了GBM细胞的体外增殖，通过诱导线粒体凋亡、抑制与上皮间质转化（EMT）相关的蛋白质水平来抑制GBM细胞的侵袭和迁移。瓜陵菜酮通过RNA测序分析表明天然香豆素受体A（PDGFRA）是该药物下调的一个潜在靶标。PDGFRA蛋白和下游介体的分析表明，瓜陵菜酮抑制了PDGFRA/MEK/ERK信号。最后，按照实验协议给予小鼠瓜陵菜酮治疗，发现其肿瘤体积减少（第28天五倍差异）和增加存活率（第27天与第36天相比，分别为对照组和瓜陵菜酮处理组）相对于对照组。因此，我们的研究表明瓜陵菜酮通过靶向PDGFRA体现出GBM细胞的抗肿瘤活性，因此提供了一种治疗GBM的候选化合物。

Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated.GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect.Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls.Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.© 2023. The Author(s).