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Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction.
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2020-05-22 , DOI: 10.1111/jcmm.15415
Yingxiao Cao 1 , Shiqi Kong 1 , Yuling Xin 1 , Yan Meng 2 , Shuling Shang 2 , Yanhui Qi 3
Affiliation  

Lestaurtinib, also called CEP‐701, is an inhibitor of tyrosine kinase, causes haematological remission in patients with AML possessing FLT3‐ITD (FLT3 gene) internal tandem duplication and strongly inhibits tyrosine kinase FLT3. Treatment with lestaurtinib modulates various signalling pathways and leads to cell growth arrest and programmed cell death in several tumour types. However, the effect of lestaurtinib on glioma remains unclear. In this study, we examined lestaurtinib and TRAIL interactions in glioma cells and observed their synergistic activity on glioma cell apoptosis. While U87 and U251 cells showed resistance to TRAIL single treatment, they were sensitized to apoptosis induced by TRAIL in the presence of lestaurtinib because of increased death receptor 5 (DR5) levels through CHOP‐dependent manner. We also demonstrated using a xenograft model of mouse that the tumour growth was absolutely suppressed because of the combined treatment compared to TRAIL or lestaurtinib treatment carried out singly. Our findings reveal a potential new strategy to improve antitumour activity induced by TRAIL in glioma cells using lestaurtinib through a mechanism dependent on CHOP.

中文翻译:


Lestaurtinib 通过 CHOP 依赖性 DR5 诱导增强 TRAIL 诱导的神经胶质瘤细胞凋亡。



Lestaurtinib,也称为 CEP-701,是一种酪氨酸激酶抑制剂,可导致具有 FLT3-ITD( FLT3基因)内部串联重复的 AML 患者的血液学缓解,并强烈抑制酪氨酸激酶 FLT3。 lestaurtinib 治疗可调节多种信号通路,导致多种肿瘤类型的细胞生长停滞和程序性细胞死亡。然而,lestaurtinib 对神经胶质瘤的作用仍不清楚。在这项研究中,我们检查了来斯塔替尼和 TRAIL 在神经胶质瘤细胞中的相互作用,并观察了它们对神经胶质瘤细胞凋亡的协同活性。虽然 U87 和 U251 细胞对 TRAIL 单一治疗表现出耐药性,但由于通过 CHOP 依赖性方式增加了死亡受体 5 (DR5) 水平,因此在来他替尼存在的情况下,它们对 TRAIL 诱导的细胞凋亡敏感。我们还使用小鼠异种移植模型证明,与单独进行 TRAIL 或 lestaurtinib 治疗相比,联合治疗绝对抑制了肿瘤生长。我们的研究结果揭示了一种潜在的新策略,通过依赖于 CHOP 的机制,使用 lestaurtinib 提高 TRAIL 在神经胶质瘤细胞中诱导的抗肿瘤活性。
更新日期:2020-07-10
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