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Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide

Hargrove, Amanda E. and Martínez, Thomas F. and Hare, Alissa A. and Kurmis, Alexis A. and Phillips, John W. and Sud, Sudha and Pienta, Kenneth J. and Dervan, Peter B. (2015) Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. PLoS ONE, 10 (11). Art. No. e0143161. ISSN 1932-6203. PMCID PMC4646452. https://resolver.caltech.edu/CaltechAUTHORS:20151201-124403066

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[img] Image (PNG) (S1 Fig. (A) Chemical structure of 1-FITC. (B) Nuclear localization of 1-FITC in VCaP cells are 24 h and 48 h incubation) - Supplemental Material
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[img] Image (PNG) (S2 Fig. Mass spectrometry data for Py-Im polyamides used) - Supplemental Material
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[img] Image (PNG) (S3 Fig. Primer sequences for qPCR analysis) - Supplemental Material
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[img] Image (PNG) (S4 Fig. Report of two-way ANOVA analysis from Prism software (GraphPad) for Comet assays in VCaP cells) - Supplemental Material
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[img] Image (PNG) (S5 Fig. (A) Table of mRNA expression levels for AR-driven genes under DHT-induced conditions in response to 10 μM polyamide 1) - Supplemental Material
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[img] Image (PNG) (S6 Fig. Connectivity map analysis of perturbagens that correlate with gene expression changes induced by polyamide 1 in LNCaP cells) - Supplemental Material
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[img] Image (PNG) (S7 Fig. Effect of topoisomerase inhibitors on gene expression in VCaP cells) - Supplemental Material
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Abstract

Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pone.0143161DOIArticle
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143161PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646452/PubMed CentralArticle
Additional Information:© 2015 Hargrove et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: July 21, 2015; Accepted: November 2, 2015; Published: November 16, 2015. The research has been supported by the National Institutes of Health (www.nih.gov, Grants R01GM027681 to PBD, F32CA156833 to AEH, F31CA159896 to TFM, F32CA173977 to AAH, and T32GM007616 to AAK) and the Prostate Cancer Foundation (www.pcf.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. All relevant data are within the paper and its Supporting Information files. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering at the California Institute of Technology, imaging was performed at the Caltech Bioimaging Center in the Beckman Institute, and sequencing was performed at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. Author Contributions: Conceived and designed the experiments: AEH TFM AAH AAK JWP SS KJP PBD. Performed the experiments: AEH TFM AAH AAK JWP SS. Analyzed the data: AEH TFM AAH AAK JWP SS KJP PBD. Contributed reagents/materials/analysis tools: AEH AAH JWP. Wrote the paper: AEH TFM AAH AAK JWP KJP PBD.
Funders:
Funding AgencyGrant Number
NIHR01GM027681
NIHF32CA156833
NIHF31CA159896
NIHF32CA173977
NIHT32GM007616
Prostate Cancer FoundationUNSPECIFIED
Issue or Number:11
PubMed Central ID:PMC4646452
Record Number:CaltechAUTHORS:20151201-124403066
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20151201-124403066
Official Citation:Hargrove AE, Martinez TF, Hare AA, Kurmis AA, Phillips JW, Sud S, et al. (2015) Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. PLoS ONE 10(11): e0143161. doi:10.1371/journal.pone.0143161
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:62505
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Dec 2015 03:08
Last Modified:03 Oct 2019 09:19

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