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Antitumor activity of a pyrrole-imidazole polyamide.


ABSTRACT: 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.

SUBMITTER: Yang F 

PROVIDER: S-EPMC3562772 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Antitumor activity of a pyrrole-imidazole polyamide.

Yang Fei F   Nickols Nicholas G NG   Li Benjamin C BC   Marinov Georgi K GK   Said Jonathan W JW   Dervan Peter B PB  

Proceedings of the National Academy of Sciences of the United States of America 20130114 5


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,  ...[more]

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