Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor α and enhancing changes in all-trans-retinoic acid-regulated gene expression

Ke Xu, Fabien Guidez, Annegret Glasow, Danna Chung, Kevin Petrie, Kimberly Stegmaier, Kan Kan Wang, Ji Zhang, Yongkui Jing, Arthur Z Zelent, Samuel Waxman

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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) α 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-RARα and RARα, 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.

Original languageEnglish (US)
Pages (from-to)7856-7865
Number of pages10
JournalCancer Research
Volume65
Issue number17
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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Co-Repressor Proteins
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Tretinoin
Ligands
Gene Expression
Cell Differentiation
Histone Deacetylase Inhibitors
Retinoids
Arsenic
Post Translational Protein Processing
Acetylation
Acute Myeloid Leukemia
Pharmaceutical Preparations
Histones
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor α and enhancing changes in all-trans-retinoic acid-regulated gene expression. / Xu, Ke; Guidez, Fabien; Glasow, Annegret; Chung, Danna; Petrie, Kevin; Stegmaier, Kimberly; Wang, Kan Kan; Zhang, Ji; Jing, Yongkui; Zelent, Arthur Z; Waxman, Samuel.

In: Cancer Research, Vol. 65, No. 17, 01.09.2005, p. 7856-7865.

Research output: Contribution to journalArticle

Xu, Ke ; Guidez, Fabien ; Glasow, Annegret ; Chung, Danna ; Petrie, Kevin ; Stegmaier, Kimberly ; Wang, Kan Kan ; Zhang, Ji ; Jing, Yongkui ; Zelent, Arthur Z ; Waxman, Samuel. / Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor α and enhancing changes in all-trans-retinoic acid-regulated gene expression. In: Cancer Research. 2005 ; Vol. 65, No. 17. pp. 7856-7865.
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AU - Xu, Ke

AU - Guidez, Fabien

AU - Glasow, Annegret

AU - Chung, Danna

AU - Petrie, Kevin

AU - Stegmaier, Kimberly

AU - Wang, Kan Kan

AU - Zhang, Ji

AU - Jing, Yongkui

AU - Zelent, Arthur Z

AU - Waxman, Samuel

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