Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells
Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells
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DOI：
10.1007/s10637-014-0076-7
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发表时间：
2014-08-01
影响因子：
3.4
通讯作者：
Kratzke, Robert A.
中科院分区：
文献类型：
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作者：
Chen, Esther Z.;Jacobson, Blake A.;Kratzke, Robert A.
错乱的帽子介导的翻译与包括间皮瘤在内的许多人类癌症的发生、维持和发展有关。在这项研究中，通过拮抗eIF4E-mRNA-CAP相互作用来破坏eIF4F复合体被评估为治疗间皮瘤的一种方法。间皮瘤细胞用4Ei-1处理，4Ei-1是一种膜透性前药，当转化为活性药物时，7-苄基鸟苷一磷酸(70n-GMP)取代eIF4F复合体中封顶的mRNAs。观察4Ei-1单独或联合培美曲塞治疗间皮瘤的集落形成情况。用4Ei-1处理细胞，观察细胞增殖情况。结合合成的帽类似物被用来研究4Ei-1暴露的裂解物中eIF4F复合体的激活强度。4Ei-1处理组克隆形成率和细胞存活率呈剂量依赖性下降。4Ei-1与培美曲塞联合治疗进一步减少了集落数。EIF4F帽复合体的形成随着4Ei-1的暴露而减少。4EI-1是一种新型前体药物，具有抑制细胞增殖、抑制集落形成、减少eIF4F与mRNA帽的结合以及增敏间皮瘤细胞对培美曲塞的作用。
Deranged cap-mediated translation is implicated in the genesis, maintenance and progression of many human cancers including mesothelioma. In this study, disrupting the eIF4F complex by antagonizing the eIF4E-mRNA-cap interaction is assessed as a therapy for mesothelioma. Mesothelioma cells were treated with 4Ei-1, a membrane permeable prodrug that when converted to the active drug, 7-benzyl guanosine monophosphate (7Bn-GMP) displaces capped mRNAs from the eIF4F complex. Colony formation was measured in mesothelioma treated with 4Ei-1 alone or combined with pemetrexed. Proliferation was examined in cells treated with 4Ei-1. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation in lysates exposed to 4Ei-1. 4Ei-1 treatment resulted in a dose dependent decrease in colony formation and cell viability. Combination therapy of 4Ei-1 with pemetrexed further reduced colony number. Formation of eIF4F cap-complex decreased in response to 4Ei-1 exposure. 4Ei-1 is a novel prodrug that reduces proliferation, represses colony formation, diminishes association of eIF4F with the mRNA cap, and sensitizes mesothelioma cells to pemetrexed.