Please use this identifier to cite or link to this item:
Title: Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa
Authors: Inoue, Satoshi
Riley, Joan
Gant, Timothy W.
Dyer, Martin J.S.
Cohen, Gerald M.
First Published: Aug-2007
Publisher: Nature Publishing Group
Citation: Leukemia, 2007, 21(8), pp.1773-82
Abstract: Several histone deacetylase inhibitors (HDACi), which have recently entered early clinical trials, exert their anti-cancer activity in part through the induction of apoptosis although the precise mechanism of this induction is not known. Induction of apoptosis by structurally diverse HDACi in primary cells from patients with chronic lymphocytic leukemia (CLL) and different leukemic cell lines was mediated by the Bcl-2 regulated intrinsic pathway and demonstrated a requirement for de novo protein synthesis. A marked time dependent induction of the pro-apoptotic BH3-only proteins, Bim, Noxa and Bmf was observed, which preceded the induction of apoptosis. A key role for both Bim and Noxa was proposed in HDACi-mediated apoptosis based on our findings that siRNA for Bim and Noxa but not Bmf largely prevented the HDACi induced loss in mitochondrial membrane potential, caspase processing and phosphatidylserine externalization. Noxa, induced by HDACi, in CLL cells and tumor cell lines, bound extensively to Mcl-1, a major anti-apoptotic Bcl-2 family member present in CLL cells. Our data strongly suggests that HDACi induce apoptosis primarily through inactivation of anti-apoptotic Bcl-2 family members by increases in Bim and Noxa and highlights these increases as a potential clinical target for CLL/lymphoma therapy.
Type: Article
Description: This is the authors' final draft of the paper published as Leukemia 2007, 21(8), pp.1773-82. The published version is available via doi:10.1038/sj.leu.2404760.
Appears in Collections:Published Articles, MRC Toxicology Unit

Files in This Item:
File Description SizeFormat 
Leukemia Merged Files for resubmission April 2.pdf1.17 MBAdobe PDFView/Open

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.