探索细胞毒性 [1,2,3] 三唑基碳硼烷先导化合物对 U87 MG 人胶质母细胞瘤细胞的细胞死亡机制,Chemical Biology & Drug Design

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探索细胞毒性 [1,2,3] 三唑基碳硼烷先导化合物对 U87 MG 人胶质母细胞瘤细胞的细胞死亡机制
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2023-02-06 , DOI: 10.1111/cbdd.14208
Catalina Alamón ₁ , Belén Dávila ₁ , Hugo Cerecetto _{1,

2} , Marcos Couto ₁

Affiliation

朝着高级神经胶质瘤药物发现方向发展，本研究旨在检测由三种基于碳硼烷基的先导化合物诱导的细胞死亡（细胞凋亡、坏死和/或自噬）的机制。为此，我们在 U87 MG 细胞中进行了流式细胞术实验，作为金标准技术，以及共聚焦显微镜和¹ H-NMR 实验作为非侵入性测定。我们从内部图书馆和相应的母体化合物中选择了三种混合先导物 ( 1–3 )，并识别出酪氨酸激酶抑制剂（拉帕替尼、舒尼替尼和厄洛替尼）以在这些实验中进行测试。使用 Annexin V-FITC/DAPI 染色的流式细胞术显示，导联1和3_{拉帕替尼主要在IC 50}剂量处理24小时后诱导U87 MG坏死；同时，hybrid 2、sunitinib 和 erlotinib 似乎在这些细胞中诱导凋亡。一般而言，共聚焦显微镜研究与流式细胞术观察到坏死细胞中细胞膜完整性的丧失和凋亡细胞中的细胞凋亡特征（即染色质浓缩）一致。最后，核磁共振结果显示，用杂交1、3或拉帕替尼处理的胶质母细胞瘤细胞显示出 CH ₂ /CH ₃信号比和胆碱信号的变化，这可能表明坏死细胞死亡机制：同时，2-、舒尼替尼或厄洛替尼处理的细胞表现出凋亡特征行为。此外，carboranyl-hybrid 2还在 U87 MG 细胞中产生自噬。

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Exploring the cell death mechanisms of cytotoxic [1,2,3]triazolylcarborane lead compounds against U87 MG human glioblastoma cells

Moving towards high-grade glioma drug discovery, this study aimed to detect the mechanism of cellular death (apoptosis, necrosis and/or autophagy) induced by three carboranyl-based lead compounds. For that, we performed in U87 MG cells, flow cytometry experiments, as the gold standard technique, as well as confocal microscopy and ¹H-NMR experiments as non-invasive assays. We selected three hybrid leads (1–3) from the in-house-library and the corresponding parent compounds, and recognized tyrosine kinase inhibitors (lapatinib, sunitinib and erlotinib) to put to the test in these experiments. Flow cytometry with Annexin V-FITC/DAPI staining showed that leads 1 and 3 and lapatinib mainly induced necrosis in U87 MG upon a 24 h treatment at IC₅₀ dose; meanwhile, hybrid 2, sunitinib and erlotinib seem to induce apoptosis in such cells. In general, confocal microscopy studies were in agreement with flow cytometry observing loss of cell membrane integrity in necrotic cells and features of apoptosis, that is, chromatin condensation, in apoptotic cells. Finally, NMR results showed that glioblastoma cells treated with hybrid 1, 3 or lapatinib displayed changes in CH₂/CH₃ signal ratio and choline signals that could indicate necrotic cell death mechanism: meanwhile, 2-, sunitinib- or erlotinib-treated cells showed apoptotic characteristic behaviors. Additionally, carboranyl-hybrid 2 also produced autophagy in U87 MG cells.

更新日期：2023-02-06

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