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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

新化合物ND-17调节JAK/STAT, PI3K/AKT和MAPK通路并抑制人T淋巴细胞白血病的发展

卷 22, 期 5, 2022

发表于: 12 April, 2022

页: [404 - 413] 页: 10

弟呕挨: 10.2174/1568009622666220304202116

价格: $65

摘要

背景:T细胞急性淋巴细胞白血病（T-ALL）是一种T细胞祖细胞的侵袭性血液恶性疾病。Janus激酶-转录信号转导与激活（JAK-STAT）信号通路在T-ALL的发展和抑制关键分子JAK2中起着重要作用，可以抑制T-ALL细胞的增殖。 目的:研究新型尼洛替尼衍生物ND-17通过与JAK2的相互作用对癌细胞的体外抗肿瘤作用。 方法:采用四氮唑试验和流式细胞仪分别评估了ND-17对细胞增殖、细胞周期和细胞凋亡的影响。此外，利用表面等离子体共振和蛋白质印迹法分析评估ND-17/JAK2的结合作用。 结果:在所有血液肿瘤细胞系中，ND-17对T-ALL细胞抑制作用最强。流式细胞仪分析显示ND-17将T-ALL细胞的细胞周期阻断在S期。尼洛替尼没有明显抑制T-ALL细胞生长或调节细胞周期。初步研究表明，细胞周期蛋白依赖的激酶/细胞周期蛋白的调控是ND-17诱导的细胞周期阻滞的原因。此外，ND-17与JAK2的结合具有很强的亲和力，更重要的是，ND-17与JAK2的ATP口袋结合的方式与强效抑制剂类似。由此可见，ND-17处理对T-ALL细胞中JAK2的磷酸化具有显著的抑制作用。在白细胞介素-6-刺激的Jurkat细胞中观察到JAK2磷酸化的增加，这被ND-17处理逆转。同时，TG- 101348与ND-17结合，对JAK2磷酸化的抑制作用进一步增强。此外，转染和敲除JAK2会改变ND-17对Jurkat细胞活力的抑制作用。此外，ND-17处理抑制了JAK/STAT、磷脂酰肌醇-3-激酶/蛋白激酶B/雷帕霉素机制性靶标、丝裂原活化蛋白激酶/细胞外信号调节蛋白激酶1和2信号通路。 结论:ND-17可能是治疗T-ALL的一种有前景的JAK2抑制剂。

关键词: ND-17, T细胞急性淋巴细胞白血病，JAK2，细胞生长，细胞周期，MAPK通路。

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