Abstract
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.
Highlights
Pyrrole imidazole (Py-Im) polyamides are non-covalent, sequence specific DNA binders that can alter DNA architecture [1, 2]
Despite the relatively large molecular weight of Py-Im polyamides, these molecules are cell permeable and localize to the cell nucleus to affect endogenous gene expression [5,6,7,8,9,10]. Due to their modular sequence specificity, Py-Im polyamides can be synthesized to target DNA sequences of similar size to a protein-DNA interaction site and used to antagonize gene expression driven by specific transcription factors [7, 9,10,11,12,13]
Polyamide 1 was evaluated for antiproliferation effects in VCaP cells using the WST-1 assay under conditions similar to the gene expression experiment
Summary
Pyrrole imidazole (Py-Im) polyamides are non-covalent, sequence specific DNA binders that can alter DNA architecture [1, 2]. Despite the relatively large molecular weight of Py-Im polyamides, these molecules are cell permeable and localize to the cell nucleus to affect endogenous gene expression [5,6,7,8,9,10]. Due to their modular sequence specificity, Py-Im polyamides can be synthesized to target DNA sequences of similar size to a protein-DNA interaction site and used to antagonize gene expression driven by specific transcription factors [7, 9,10,11,12,13]. One such transcription factor that has been studied previously is the androgen receptor (AR) [9].
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