Temozolomide treatment combined with AZD3463 shows synergistic effect in glioblastoma cells
Temozolomide treatment combined with AZD3463 shows synergistic effect in glioblastoma cells
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DOI：
10.1016/j.bbrc.2020.10.058
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发表时间：
2020-12-17
影响因子：
3.1
通讯作者：
Avci, Cigir Biray
中科院分区：
文献类型：
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作者：
Bagca, Bakiye Goker;Ozates, Neslihan Pinar;Avci, Cigir Biray
替莫唑胺 (TMZ) 用于胶质母细胞瘤 (GBM) 患者的标准治疗方案。然而，一些 GBM 患者对 TMZ 治疗没有反应。由于 TMZ 耐药性，GBM 治疗中的联合治疗药物引起了相当大的兴趣。本研究旨在确定 TMZ 和 AZD3463 对 T98G GBM 细胞活力的组合效应。使用WST-8测定法测定化合物的细胞毒性作用。流式细胞术用于测定治疗后的细胞凋亡和细胞周期概况。实时PCR用于鉴定治疗后PI3K/AKT信号通路中基因的mRNA表达。孵育 48 小时后，TMZ 和 AZD3463 的 IC50 浓度分别为 1.54 mM 和 529 nM。联合治疗显示出对降低 GBM 细胞活力的协同作用。 TMZ、AZD3463 和联合治疗中的每一种均诱导细胞凋亡。单独或联合使用这些药物的治疗可导致细胞周期停滞在不同的阶段。 TMZ 和 AZD3463 单独或联合治疗可下调 PI3K/AKT 信号通路中基因的 mRNA 表达。 TMZ 与 AZD3463 的组合可能会提高 GBM 细胞中单一 TMZ 治疗的疗效，因为导致耐药性和瘤内异质性的 PI3K/AKT 信号通路中的基因表达减少。 (C) 2020 Elsevier Inc. 保留所有权利。
Temozolomide (TMZ) is used in the standard therapy regimen for patients with glioblastoma (GBM). However, some GBM patients do not respond to TMZ therapy. The combining therapeutic agents in GBM treatment are attracting considerable interest due to TMZ resistance. This study aims to identify the combinatorial effect of TMZ and AZD3463 on the viability of the T98G GBM cells. The cytotoxic effects of compounds were determined by using WST-8 assay. Flow cytometry was used to determine apoptosis and cell cycle profiles after treatments. Real-time PCR was used to identify mRNA expression of genes in the PI3K/AKT signaling pathway after treatments. IC50 concentrations of TMZ and AZD3463 were found to be 1.54 mM and 529 nM after incubation for 48 h, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. Each one of TMZ, AZD3463, and combination treatments induced apoptosis. Treatments, either alone or the combination of these agents, caused the cell cycle arrest in distinct phases. TMZ and AZD3463 treatments, either alone or in combination, downregulated mRNA expression of genes in the PI3K/AKT signaling pathway. The combination of TMZ with AZD3463 may increase the efficacy of single TMZ treatment in GBM cells due to decreased expression of genes in the PI3K/AKT signaling pathway that is responsible for drug resistance and intratumoral heterogeneity. (C) 2020 Elsevier Inc. All rights reserved.