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Benzodithiophenes Potentiate Differentiation of Acute Promyelocytic Leukemia Cells by Lowering the Threshold for Ligand-Mediated Corepressor/Coactivator Exchange with Retinoic Acid Receptor and Enhancing Changes in all-trans-Retinoic Acid–Regulated Gene Expression

¹ Section of Hemato-Oncology, Institute of Cancer Research, London, United Kingdom; ² Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ³ State Key Lab for Medical Genomics, Ruijin Hospital, Shanghai Second Medical University, and ⁴ Health Science Center, Shanghai Institutes of Biological Science, Chinese Academy of Science and Shanghai Second Medical University, Shanghai, China; and ⁵ Department of Medicine, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Samuel Waxman, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029. Phone: 212-241-6771; Fax: 212-996-5787; E-mail: samuel.waxman{at}mssm.edu.

Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which dramatically responds to all-trans-retinoic acid (ATRA). Recent studies have indicated that combinatorial use of retinoid and nonretinoid compounds, such as histone deacetylase inhibitors, arsenics, and PKA agonists, has higher therapeutic value in this disease and potentially in other malignancies. In a screen of 370 compounds, we identified benzodithiophene analogues as potent enhancers of ATRA-induced APL cell differentiation. These effects were not associated with changes in global histone acetylation and, for the most potent compounds, were exerted at very low nanomolar concentrations, and were paralleled by enhancement of some, but not all, ATRA-modulated gene expressions. Investigating the mechanism underlying the effects of these drugs on ATRA-induced APL cell differentiation, we have shown that benzodithiophenes enhance ATRA-mediated dissociation and association of corepressor N-CoR and coactivator p300 acetyltransferase, respectively, with retinoic acid receptor (RAR) proteins. These data suggest that benzodithiophenes act at the level of receptor activation, possibly by affecting posttranslational modification of the receptor (and/or coregulators), thus leading to an enhancement in ATRA-mediated effects on gene expression and APL cell differentiation. Given the specificities of these low benzodithiophene concentrations for PML-RAR and RAR, these drugs may be useful for combinatorial differentiation therapy of APL and possibly other acute myelogenous leukemia subtypes in which the overall ATRA signaling is suppressed.