CLIN CANCER RES:靶向PCNA小分子的抗肿瘤活性

2018-12-19 MedSci MedSci原创

增殖细胞核抗原(PCNA)在调节DNA合成和修复中起重要作用,是肿瘤细胞生长和存活必不可少的。之前的研究报道了一种新的癌症相关PCNA型(称为caPCNA),其在许多肿瘤细胞和肿瘤组织中广泛表达,但在非恶性细胞中不表达不显着。caPCNA的L126-Y133区域在结构上发生了改变,并且更容易发生蛋白质-蛋白质相互作用。携带L126-Y133序列的细胞可渗透的肽可以阻断癌细胞中PCNA作用,并选择性

增殖细胞核抗原(PCNA)在调节DNA合成和修复中起重要作用,是肿瘤细胞生长和存活必不可少的。之前的研究报道了一种新的癌症相关PCNA型(称为caPCNA),其在许多肿瘤细胞和肿瘤组织中广泛表达,但在非恶性细胞中不表达不显着。caPCNA的L126-Y133区域在结构上发生了改变,并且更容易发生蛋白质-蛋白质相互作用。携带L126-Y133序列的细胞可渗透的肽可以阻断癌细胞中PCNA作用,并选择性地杀死癌细胞和异种移植肿瘤。基于这些发现,CLIN CANCER RES近期发表了一篇文章,寻找靶向该肽区域的小分子作为潜在的广谱抗癌药物。

作者发现了有效的PCNA抑制剂(AOH1160)并且研究其治疗效果和潜在的毒性。研究结果表明,AOH1160可以选择性地杀死许多类型的肿瘤细胞,而不会对非恶性细胞产生显着毒性。从机制上讲,AOH1160干扰DNA复制,阻断同源重组介导的DNA修复,并导致细胞周期停滞。可以诱导肿瘤细胞凋亡并使其对顺铂治疗敏感。AOH1160可以口服并抑制肿瘤生长。重要的是,在有效剂量的2.5倍时不会引起显着的毒性。

文章最后认为,这些结果证明AOH1160具有治疗效果,可以作为癌症广谱治疗剂的潜在药物。

原始出处:

Long Gu, Robert Lingeman, et al. The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA. CLIN CANCER RES. December 2018 doi: 10.1158/1078-0432.CCR-18-0592

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    2019-03-11 宋威
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    2018-12-20 124676b8m54(暂无昵称)

    可以可以

    0

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    2018-12-19 1ddf0692m34(暂无匿称)

    学习了,谢谢分享

    0