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Antitumor activity of a pyrrole-imidazole polyamide

Yang, Fei and Nickols, Nicholas G. and Li, Benjamin C. and Marinov, Georgi K. and Said, Jonathan W. and Dervan, Peter B. (2013) Antitumor activity of a pyrrole-imidazole polyamide. Proceedings of the National Academy of Sciences of the United States of America, 110 (5). pp. 1863-1868. ISSN 0027-8424. PMCID PMC3562772. doi:10.1073/pnas.1222035110. https://resolver.caltech.edu/CaltechAUTHORS:20130308-091951458

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1222035110DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562772/PubMed CentralArticle
http://www.pnas.org/content/110/5/1863/suppl/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Marinov, Georgi K.0000-0003-1822-7273
Dervan, Peter B.0000-0001-8852-7306
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.
Funders:
Funding AgencyGrant Number
NIHGM-27681
NIHHG004576
Prostate Cancer FoundationUNSPECIFIED
UCLA Jonsson Cancer Center FoundationUNSPECIFIED
Subject Keywords:minor groove binder; small molecule transcription inhibitor; ChIP-Seq
Issue or Number:5
PubMed Central ID:PMC3562772
DOI:10.1073/pnas.1222035110
Record Number:CaltechAUTHORS:20130308-091951458
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130308-091951458
Official Citation:Fei Yang, Nicholas G. Nickols, Benjamin C. Li, Georgi K. Marinov, Jonathan W. Said, and Peter B. Dervan Antitumor activity of a pyrrole-imidazole polyamide PNAS 2013 110 (5) 1863-1868; published ahead of print January 14, 2013, doi:10.1073/pnas.1222035110
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37407
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Apr 2013 19:10
Last Modified:09 Nov 2021 23:28

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