Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide

Amanda E. Hargrove, Thomas F. Martinez, Alissa A. Hare, Alexis A. Kurmis, John W. Phillips, Sudha Sud, Kenneth J. Pienta, Peter B. Dervan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0143161
JournalPloS one
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hargrove, A. E., Martinez, T. F., Hare, A. A., Kurmis, A. A., Phillips, J. W., Sud, S., Pienta, K. J., & Dervan, P. B. (2015). Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide. PloS one, 10(11), [e0143161]. https://doi.org/10.1371/journal.pone.0143161