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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Models and Technologies

Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome

Noël J.-M. Raynal, Elodie M. Da Costa, Justin T. Lee, Vazganush Gharibyan, Saira Ahmed, Hanghang Zhang, Takahiro Sato, Gabriel G. Malouf and Jean-Pierre J. Issa
Noël J.-M. Raynal
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.Département de pharmacologie et physiologie, Université de Montréal and Sainte-Justine University Hospital Research Center, Montréal, Québec, Canada.
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  • For correspondence: noel.raynal@umontreal.ca
Elodie M. Da Costa
Département de pharmacologie et physiologie, Université de Montréal and Sainte-Justine University Hospital Research Center, Montréal, Québec, Canada.
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Justin T. Lee
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
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Vazganush Gharibyan
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Saira Ahmed
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Hanghang Zhang
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
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Takahiro Sato
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
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Gabriel G. Malouf
Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France.
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Jean-Pierre J. Issa
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
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DOI: 10.1158/1535-7163.MCT-16-0588 Published February 2017
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Abstract

Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397–407. ©2016 AACR.

This article is featured in Highlights of This Issue, p. 261

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received September 1, 2016.
  • Revision received October 28, 2016.
  • Accepted November 17, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 16 (2)
February 2017
Volume 16, Issue 2
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Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome
Noël J.-M. Raynal, Elodie M. Da Costa, Justin T. Lee, Vazganush Gharibyan, Saira Ahmed, Hanghang Zhang, Takahiro Sato, Gabriel G. Malouf and Jean-Pierre J. Issa
Mol Cancer Ther February 1 2017 (16) (2) 397-407; DOI: 10.1158/1535-7163.MCT-16-0588

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Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome
Noël J.-M. Raynal, Elodie M. Da Costa, Justin T. Lee, Vazganush Gharibyan, Saira Ahmed, Hanghang Zhang, Takahiro Sato, Gabriel G. Malouf and Jean-Pierre J. Issa
Mol Cancer Ther February 1 2017 (16) (2) 397-407; DOI: 10.1158/1535-7163.MCT-16-0588
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Molecular Cancer Therapeutics
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