Histone deacetylase inhibitors specifically kill nonproliferating tumour cells

Burgess, Andrew, Ruefli, Astrid, Beamish, Heather, Warrener, Robyn, Saunders, Nicholas, Johnstone, Ricky and Gabrielli, Brian (2004) Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene, 23 40: 6693-6701. doi:10.1038/sj.onc.1207893


Author Burgess, Andrew
Ruefli, Astrid
Beamish, Heather
Warrener, Robyn
Saunders, Nicholas
Johnstone, Ricky
Gabrielli, Brian
Title Histone deacetylase inhibitors specifically kill nonproliferating tumour cells
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2004
Sub-type Article (original research)
DOI 10.1038/sj.onc.1207893
Volume 23
Issue 40
Start page 6693
End page 6701
Total pages 9
Place of publication London, United Kingdom
Publisher Nature
Collection year 2004
Language eng
Abstract Conventional chemotherapeutic drugs target proliferating cells, relying on often small differences in drug sensitivity of tumour cells compared to normal tissue to deliver a therapeutic benefit. Consequently, they have significant limiting toxicities and greatly reduced efficacy against nonproliferating compared to rapidly proliferating tumour cells. This lack of selectivity and inability to kill nonproliferating cells that exist in tumours with a low mitotic index are major failings of these drugs. A relatively new class of anticancer drugs, the histone deacetylase inhibitors (HDI), are selectively cytotoxic, killing tumour and immortalized cells but normal tissue appears resistant. Treatment of tumour cells with these drugs causes both G1 phase cell cycle arrest correlated with increase p21 expression, and cell death, but even the G1 arrested cells died although the onset of death was delayed. We have extended these observations using cells that were stably arrested by either serum starvation or expression of the cyclin-dependent kinase inhibitor p16(ink4a). We report that histone deacetylase inhibitors have similar cytotoxicity towards both proliferating and arrested tumour and immortalized cells, although the onset of apoptosis is delayed by 24 h in the arrested cells. Both proliferating and arrested normal cells are unaffected by HDI treatment. Thus, the histone deacetylase inhibitors are a class of anticancer drugs that have the desirable features of being tumour-selective cytotoxic drugs that are equally effective in killing proliferating and nonproliferating tumour cells and immortalized cells. These drugs have enormous potential for the treatment of not only rapidly proliferating tumours, but tumours with a low mitotic index.
Keyword Apoptosis
Cell cycle
Chemotherapy
Histone deacetylase inhibitors
Quiescent
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 04:07:00 EST