Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1863-8. doi: 10.1073/pnas.1222035110. Epub 2013 Jan 14.
Many cancer therapeutics target DNA and exert cytotoxicity through the induction of DNA damage and inhibition of transcription. We report that a DNA minor groove binding hairpin pyrrole-imidazole (Py-Im) polyamide interferes with RNA polymerase II (RNAP2) activity in cell culture. Polyamide treatment activates p53 signaling in LNCaP prostate cancer cells without detectable DNA damage. Genome-wide mapping of RNAP2 binding shows reduction of occupancy, preferentially at transcription start sites, but occupancy at enhancer sites is unchanged. Polyamide treatment results in a time- and dose-dependent depletion of the RNAP2 large subunit RPB1 that is preventable with proteasome inhibition. This polyamide demonstrates antitumor activity in a prostate tumor xenograft model with limited host toxicity.
许多癌症治疗药物针对 DNA，并通过诱导 DNA 损伤和抑制转录来发挥细胞毒性作用。我们报告称，一种 DNA 小沟结合发夹吡咯-咪唑（Py-Im）聚酰胺在细胞培养中干扰 RNA 聚合酶 II（RNAP2）的活性。聚酰胺处理激活 LNCaP 前列腺癌细胞中的 p53 信号通路，而没有检测到 DNA 损伤。RNAP2 结合的全基因组图谱显示，结合物的占有率降低，优先在转录起始位点，但增强子位点的占有率不变。聚酰胺处理导致 RNAP2 大亚基 RPB1 的时间和剂量依赖性耗竭，而蛋白酶体抑制可预防这种耗竭。这种聚酰胺在前列腺肿瘤异种移植模型中具有抗肿瘤活性，且宿主毒性有限。
