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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Humans
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Imidazoles / chemistry
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Immunoblotting
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Nylons / chemistry
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Nylons / metabolism
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Nylons / pharmacology*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / prevention & control*
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Proteasome Inhibitors / pharmacology
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / metabolism
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Pyrroles / chemistry
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RNA Polymerase II / antagonists & inhibitors
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RNA Polymerase II / metabolism
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Signal Transduction / drug effects
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Time Factors
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Transcription, Genetic / drug effects
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays*
Substances
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Antineoplastic Agents
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Il2rg protein, mouse
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Imidazoles
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Interleukin Receptor Common gamma Subunit
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Nylons
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Proteasome Inhibitors
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Protein Subunits
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Pyrroles
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Tumor Suppressor Protein p53
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imidazole
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RNA Polymerase II