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.
Additional Information
© 2013 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Peter B. Dervan, December 17, 2012 (sent for review October 19, 2012). Published online before print January 14, 2013. We thank Rochelle Diamond of the Caltech Flow Cytometry Cell Sorting Facility for help with flow cytometry experimental setup and data acquisition; and Dr. Janet Baer, Dr. Karen L. Lencioni, and Gwen E. Williams for helpful discussions and technical assistance with animal experiments. This work was supported in part by the National Institutes of Health Grants GM27681 and HG004576, and by the Prostate Cancer Foundation. N.G.N. acknowledges the Jonsson Cancer Center Foundation at University of California at Los Angeles for continued support. Author contributions: F.Y., N.G.N., G.K.M., and P.B.D. designed research; F.Y., N.G.N., B.C.L., and J.W.S. performed research; F.Y., N.G.N., and B.C.L. contributed new reagents/analytic tools; F.Y., N.G.N., B.C.L., G.K.M., and P.B.D. analyzed data; and F.Y., N.G.N., and P.B.D. wrote the paper. The authors declare no conflict of interest. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE43253). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1222035110/-/DCSupplemental.Attached Files
Published - PNAS-2013-Yang-1863-8.pdf
Supplemental Material - pnas.201222035SI.pdf
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Additional details
- PMCID
- PMC3562772
- Eprint ID
- 37407
- Resolver ID
- CaltechAUTHORS:20130308-091951458
- GM-27681
- NIH
- HG004576
- NIH
- Prostate Cancer Foundation
- UCLA Jonsson Cancer Center Foundation
- Created
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2013-04-11Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field