Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.
Fiche publication
Date publication
février 2017
Journal
Molecular cancer therapeutics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MALOUF Gabriel
Tous les auteurs :
Raynal NJ, Da Costa EM, Lee JT, Gharibyan V, Ahmed S, Zhang H, Sato T, Malouf GG, Issa JJ
Lien Pubmed
Résumé
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.
Mots clés
Antineoplastic Agents, pharmacology, Cell Line, Tumor, Cluster Analysis, Colonic Neoplasms, drug therapy, Computational Biology, methods, DNA Methylation, drug effects, Drug Discovery, Drug Interactions, Drug Repositioning, Drug Screening Assays, Antitumor, Epigenesis, Genetic, drug effects, Epigenomics, methods, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, drug effects, Genes, Reporter, High-Throughput Screening Assays, Histone Deacetylase Inhibitors, pharmacology, Humans, Reproducibility of Results, Small Molecule Libraries
Référence
Mol. Cancer Ther.. 2017 02;16(2):397-407