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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

聚异戊二烯基化的半胱氨酰胺抑制剂可耗尽K-Ras并诱导肺癌细胞中caspase依赖性凋亡。

卷 19, 期 10, 2019

页: [838 - 851] 页: 14

弟呕挨: 10.2174/1568009619666190325144636

价格: $65

摘要

背景：携带突变诱导的Ras信号失调的非小细胞肺癌（NSCLC）存在一些最难处理的病例，因为直接靶向组成型活性突变Ras蛋白并未产生临床上有用的药物。因此，调节Ras活性以靶向治疗癌症仍然是迫切的医疗保健需求。 目的：在当前研究中，我们使用带有K-Ras和/或其他突变基因的NSCLC细胞组研究了新型化合物，即聚异戊二烯基半胱氨酰胺抑制剂（PCAIs）的抗癌分子机制。 方法：测定PCAIs对细胞内K-Ras水平，细胞活力，凋亡，球状体和集落形成的影响。 结果：用PCAI，NSL-RD-035，NSL-BA-036，NSL-BA-040和NSL-BA-055处理肺癌细胞会导致浓度依赖性细胞死亡，这两种K-Ras突变体（A549 ，NCI-H460和NCI-H1573），N-Ras突变体（NCI-H1299）和其他（NCI-H661，NCI-H1975，NCIH1563）NSCLC细胞。 1.0 -10μM的PCAIs诱导3D球形培养物的变性，抑制克隆细胞的生长，并通过外部途径诱导明显的细胞凋亡。相对于GAPDH，最强的PCAI（NSL-BA-055）浓度为5μM诱导的caspase-3 / 7活性增加了7倍，K-Ras蛋白水平的选择性消耗相对于APD细胞中的GAPDH减少了75％。与PCAIs诱导的细胞凋亡相关。 NSL-BA-040和NSL-BA-055也诱导MAP激酶（ERK 1/2）的磷酸化。 结论：综上所述，PCAIs可能作为靶向疗法，可能通过破坏Ras介导的生长信号来抑制NSCLC进展。

关键词: K-Ras，PCAI，凋亡，肺癌，非小细胞肺癌（NSCLC），Ras蛋白。

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