Defining the chemotherapeutic targets of Histone Deacetylase inhibitors

Gabrielli, B. G., Warrener, R. M., Burgess, A. J. and Beamish, H. J. (2004) Defining the chemotherapeutic targets of Histone Deacetylase inhibitors. Annals New York Academy of Sciences, 1030 627-635. doi:10.1196/annals.1329.073

Author Gabrielli, B. G.
Warrener, R. M.
Burgess, A. J.
Beamish, H. J.
Title Defining the chemotherapeutic targets of Histone Deacetylase inhibitors
Formatted title
Defining the chemotherapeutic targets of Histone Deacetylase inhibitors
Journal name Annals New York Academy of Sciences   Check publisher's open access policy
ISSN 0077-8923
ISBN 1-57331-573-7
Publication date 2004
Sub-type Article (original research)
DOI 10.1196/annals.1329.073
Volume 1030
Start page 627
End page 635
Total pages 9
Place of publication United States
Publisher New York Academy of Sciences
Collection year 2004
Language eng
Subject C1
270106 Cell Development (incl. Cell Division and Apoptosis)
730108 Cancer and related disorders
Abstract The use of many conventional chemotherapeutic drugs is often severely restricted due to dose-limiting toxicities, as these drugs target the destruction of the proliferating fraction of cells, often with little specificity for tumor cells over proliferating normal body tissue. Many newer drugs attempt to overcome this shortcoming by targeting defective gene products or cellular mechanisms that are specific to the tumor, thereby minimizing the toxicity to normal tissue. Histone deacetylase inhibitors are an example of this type of tumor-directed drug, having significant toxicity for tumors but minimal effects on normal tissue. These drugs can affect the transcriptional program by modifying chromatin structure, but it is not yet clear whether specific transcriptional changes are directly responsible for their tumor-selective toxicity. Recent evidence suggests that transcriptional changes underlie their cytostatic activity, although this is not tumor-selective and affects all proliferating cells. Here we present evidence that supports an alternative mechanism for the tumor-selective cytotoxicity of histone deacetylase inhibitors. The target is still likely to be the chromatin histones, but rather than transcriptional changes due to modification of the transcriptionally active euchromatin, we propose that hyperacetylation and disruption of the transcriptionally inactive heterochromatin, particularly the centromeric heterochromatin, and the inability of tumor cells to cell cycle arrest in response to a specific checkpoint, underlies the tumor-selective cytotoxicity of these drugs.
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 04:06:56 EST