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Activity of a Py–Im Polyamide Targeted to the Estrogen Response Element

Nickols, Nicholas G. and Szablowski, Jerzy O. and Hargrove, Amanda E. and Li, Benjamin C. and Raskatov, Jevgenij A. and Dervan, Peter B. (2013) Activity of a Py–Im Polyamide Targeted to the Estrogen Response Element. Molecular Cancer Therapeutics, 12 (5). pp. 675-684. ISSN 1535-7163. PMCID PMC3651785. doi:10.1158/1535-7163.MCT-12-1040. https://resolver.caltech.edu/CaltechAUTHORS:20130624-141110107

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Abstract

Pyrrole-imidazole (Py–Im) polyamides are a class of programmable DNA minor groove binders capable of modulating the activity of DNA-binding proteins and affecting changes in gene expression. Estrogen receptor alpha (ERα) is a ligand-activated hormone receptor that binds as a homodimer to estrogen response elements (ERE) and is a driving oncogene in a majority of breast cancers. We tested a selection of structurally similar Py–Im polyamides with differing DNA sequence specificity for activity against 17β-estadiol (E2)–induced transcription and cytotoxicity in ERα positive, E2-stimulated T47DKBluc cells, which express luciferase under ERα control. The most active polyamide targeted the sequence 5′-WGGWCW-3′ (W = A or T), which is the canonical ERE half site. Whole transcriptome analysis using RNA-Seq revealed that treatment of E2-stimulated breast cancer cells with this polyamide reduced the effects of E2 on the majority of those most strongly affected by E2 but had much less effect on the majority of E2-induced transcripts. In vivo, this polyamide circulated at detectable levels following subcutaneous injection and reduced levels of ER-driven luciferase expression in xenografted tumors in mice after subcutaneous compound administration without significant host toxicity.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1535-7163.MCT-12-1040DOIArticle
http://mct.aacrjournals.org/content/12/5/675PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651785/PubMed CentralArticle
http://mct.aacrjournals.org/content/12/5/675/suppl/DC1PublisherSupplementary Data
ORCID:
AuthorORCID
Szablowski, Jerzy O.0000-0001-7851-5408
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2013 American Association for Cancer Research. Received October 29, 2012; revised February 8, 2013; accepted February 15, 2013; published Online First February 26, 2013. The authors thank Drs. Janet Baer, Dr. Karen L. Lencioni, and Gwen E. Williams for helpful discussions and technical assistance with animal experiments. Sequencing was conducted at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. This work was supported in large part by the NIH Grant GM-51747. N.G. Nickols received support from the Jonsson Cancer Center Foundation at UCLA. J.O. Szablowski and B.C. Li were supported by NIH GM-51747. J.A. Raskatov received postdoctoral support from the Alexander von Humboldt foundation. A.E. Hargrove received postdoctoral support from the California Tobacco-Related Disease Research Program (19FT-0105) and the NIH (NRSA number 1F32CA156833). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. N.G. Nickols and J.O. Szablowski contributed equally to this work. Authors' Contributions: Conception and design: N.G. Nickols, J.O. Szablowski, J.A. Raskatov, P.B. Dervan Development of methodology: N.G. Nickols, J.O. Szablowski, B.C. Li, P.B. Dervan Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): N.G. Nickols, J.O. Szablowski, A.E. Hargrove, B.C. Li Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): N.G. Nickols, J.O. Szablowski, A.E. Hargrove, J.A. Raskatov, P.B. Dervan Writing, review, and/or revision of the manuscript: N.G. Nickols, J.O. Szablowski, A.E. Hargrove, B.C. Li, J.A. Raskatov, P.B. Dervan Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): N.G. Nickols, J.O. Szablowski, P.B. Dervan Study supervision: P.B. Dervan No potential conflicts of interest were disclosed.
Funders:
Funding AgencyGrant Number
NIHGM-51747
UCLA Jonsson Cancer Center FoundationUNSPECIFIED
Alexander von Humboldt foundationUNSPECIFIED
California Tobacco-Related Disease Research Program19FT-0105
NIH Predoctoral Fellowship1F32CA156833
Issue or Number:5
PubMed Central ID:PMC3651785
DOI:10.1158/1535-7163.MCT-12-1040
Record Number:CaltechAUTHORS:20130624-141110107
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130624-141110107
Official Citation:Activity of a Py–Im Polyamide Targeted to the Estrogen Response Element Nicholas G. Nickols, Jerzy O. Szablowski, Amanda E. Hargrove, Benjamin C. Li, Jevgenij A. Raskatov, and Peter B. Dervan Mol Cancer Ther May 2013 12:675-684; Published OnlineFirst February 26, 2013; doi:10.1158/1535-7163.MCT-12-1040
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39057
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:24 Jun 2013 22:27
Last Modified:09 Nov 2021 23:42

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