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A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma has Potent Anti-tumor Activity

Mysore, Veena S. and Szablowski, Jerzy and Dervan, Peter B. and Frost, Patrick J. (2016) A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma has Potent Anti-tumor Activity. Molecular Cancer Research, 14 (3). pp. 253-266. ISSN 1541-7786. PMCID PMC4794370. http://resolver.caltech.edu/CaltechAUTHORS:20160203-085435947

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Abstract

Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained by the differential expression of the regulatory prolyl hydroxylase isoforms. The anti–multiple myeloma effects of a sequence-specific DNA-binding pyrrole-imidazole (Py-Im) polyamide (HIF-PA), which disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable with that of HIFs. Most of the multiple myeloma cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O_2-dependent activation of HIFα using polyamides.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1541-7786.MCR-15-0361DOIArticle
http://mcr.aacrjournals.org/content/14/3/253PublisherArticle
http://mcr.aacrjournals.org/content/14/3/253/suppl/DC1PublisherSupplementary Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794370/PubMed CentralArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2016 American Association for Cancer Research. Received August 26, 2015. Revision received December 4, 2015. Accepted January 14, 2016. Published Online First January 22, 2016. This work was supported by a MERIT grant 1I01BX001532 (to P.J. Frost) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service and a NIH GM051747 grant (to P.B. Dervan). 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: V.S. Mysore, J. Szablowski, P. B. Dervan, P.J. Frost Development of methodology: V.S. Mysore, P.J. Frost Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): V.S. Mysore, J. Szablowski, P.J. Frost Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): V.S. Mysore, P.J. Frost Writing, review, and/or revision of the manuscript: V.S. Mysore, J. Szablowski, P.B. Dervan, P. J. Frost Study supervision: P. B. Dervan, P.J. Frost
Funders:
Funding AgencyGrant Number
Department of Veterans Affairs1I01BX001532
NIHGM051747
PubMed Central ID:PMC4794370
Record Number:CaltechAUTHORS:20160203-085435947
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160203-085435947
Official Citation:A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity Veena S. Mysore, Jerzy Szablowski, Peter B. Dervan, and Patrick J. Frost Mol Cancer Res March 2016 14:253-266; Published OnlineFirst January 22, 2016; doi:10.1158/1541-7786.MCR-15-0361
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64183
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:03 Feb 2016 20:20
Last Modified:18 Jul 2017 20:03

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