Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.
Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.
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DOI：
10.1371/journal.pone.0143161
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dervan PB
中科院分区：
文献类型：
--
作者：
Hargrove AE;Martinez TF;Hare AA;Kurmis AA;Phillips JW;Sud S;Pienta KJ;Dervan PB
吡咯-咪唑（Py-Im）聚酰胺是一种高亲和力的DNA结合小分子，可以抑制蛋白质-DNA相互作用。在VCaP细胞（一种过表达AR和TMPRSS 2-ERG基因融合体的人前列腺癌细胞系）中，雄激素反应元件（ARE）靶向的Py-Im聚酰胺显著下调AR驱动的基因表达。聚酰胺暴露于VCaP细胞减少增殖而不引起DNA损伤。Py-Im聚酰胺治疗还减少了VCaP小鼠异种移植模型中的肿瘤生长。除了对AR调节的转录的影响之外，RNA-seq分析还揭示了抑制拓扑异构酶-DNA结合作为有助于聚酰胺在细胞培养物和异种移植物中的抗肿瘤作用的潜在机制。这些研究支持Py-Im聚酰胺靶向前列腺癌中转录调控的多个方面而没有遗传毒性应激的治疗潜力。
Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.