Close menu

SURE

Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha 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 and Waxman, Samuel (2005) Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer research, 65 (17). pp. 7856-65. ISSN 0008-5472

Item Type: Article

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) alpha 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-RARalpha and RARalpha, 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.

[img] PDF
2005 Benzodithiophenes Potentiate Differentiation of Acute Promyelocytic Leukemia Cells.pdf - Published Version
Restricted to Repository staff only

Download (815kB)

More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12424
Identification Number: https://doi.org/10.1158/0008-5472.CAN-05-1056
ISSN: 0008-5472
URI: http://sure.sunderland.ac.uk/id/eprint/12424
Official URL: https://cancerres.aacrjournals.org/content/65/17/7...

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 10:16
Last Modified: 30 Sep 2020 10:48

Contributors

Author: Kevin Petrie ORCID iD
Author: Ke Xu
Author: Fabien Guidez
Author: Annegret Glasow
Author: Danna Chung
Author: Kimberly Stegmaier
Author: Kan-Kan Wang
Author: Ji Zhang
Author: Yongkui Jing
Author: Arthur Zelent
Author: Samuel Waxman

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

Actions (login required)

View Item (Repository Staff Only) View Item (Repository Staff Only)