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An HRE-binding Py-Im polyamide impairs hypoxic signaling in tumors

Szablowski, Jerzy O. and Raskatov, Jevgenij A. and Dervan, Peter B. (2016) An HRE-binding Py-Im polyamide impairs hypoxic signaling in tumors. Molecular Cancer Therapeutics, 15 (4). pp. 608-617. ISSN 1535-7163. PMCID PMC4873353. doi:10.1158/1535-7163.MCT-15-0719. https://resolver.caltech.edu/CaltechAUTHORS:20160112-091557715

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Abstract

Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration, and cancer. Hypoxia-inducible factor-1 (HIF1), a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis, and cell survival. Pyrrole-imidazole polyamide 1 has been shown to inhibit HIF1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels, and suppresses tumor growth. Tumors treated with 1 show no increase in HIF1α and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF1α-positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF1 has potent antitumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1535-7163.MCT-15-0719DOIArticle
http://mct.aacrjournals.org/content/15/4/608/suppl/DC1PublisherSupplementary Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873353PubMed CentralArticle
ORCID:
AuthorORCID
Szablowski, Jerzy O.0000-0001-7851-5408
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2015 American Association for Cancer Research. Received August 27, 2015. Revision received November 30, 2015. Accepted December 11, 2015. Published Online First December 30, 2015. The authors thank Caltech OLAR for technical assistance with animal experiments and TPCL (UCLA) for assisting with IHC. The authors also thank Drs. Nora Rozengurt and Dinesh Rao (UCLA) for helpful suggestions, discussion and preliminary pathologic evaluation of tumor sections and Drs. Nicholas Nickols and Bogdan Olenyuk for helpful discussions and suggestions. This work was supported by the NIH grant GM-51747. J.O. Szablowski was supported by NIH GM-51747. J.A. Raskatov received postdoctoral support from the Alexander von Humboldt Foundation. 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. Authors' Contributions: Conception and design: J.O. Szablowski, J.A. Raskatov, P.B. Dervan Development of methodology: J.O. Szablowski, J.A. Raskatov Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.O. Szablowski, J.A. Raskatov Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.O. Szablowski, J.A. Raskatov, P.B. Dervan Writing, review, and/or revision of the manuscript: J.O. Szablowski, J.A. Raskatov, P.B. Dervan Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.O. Szablowski, J.A. Raskatov Study supervision: P.B. Dervan. No potential conflicts of interest were disclosed.
Funders:
Funding AgencyGrant Number
NIHGM-51747
Alexander von Humboldt FoundationUNSPECIFIED
Subject Keywords:hypoxic signaling, angiogenesis, Py-Im polyamide, phenotypic mechanism, gene expression
Issue or Number:4
PubMed Central ID:PMC4873353
DOI:10.1158/1535-7163.MCT-15-0719
Record Number:CaltechAUTHORS:20160112-091557715
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160112-091557715
Official Citation:An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors Jerzy O. Szablowski, Jevgenij A. Raskatov, and Peter B. Dervan Mol Cancer Ther April 2016 15:608-617; Published OnlineFirst December 30, 2015; doi:10.1158/1535-7163.MCT-15-0719
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:63578
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Jan 2016 17:47
Last Modified:11 May 2022 22:35

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