Abstract
Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21+/+ and p21−/− cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.
Footnotes
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↵1 Current address: School of Chemical and Biomedical Sciences, Central Queensland University, Rockhampton, Queensland, Australia.
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This work was supported by a New Faculty Grant from the University of Queensland, the National Health and Medical Research Council of Australia and the NSW Cancer Council. A.B. is supported by a University of Queensland Postgraduate Scholarship. B.G. is an Australian Research Council Fellow.
- Abbreviations:
- HDI
- histone deacetylase inhibitor
- cdk
- cyclin-dependent kinase
- ABHA
- azelaic bishydroxamic acid
- IPTG
- isopropyl β-d-thiogalactoside
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
- PBS
- phosphate-buffered saline
- FACS
- fluorescence-activated cell sorting
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- PARP
- poly ADP-ribose polymerase
- Z-DEVD-FMK
- benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone
- Received April 9, 2001.
- Accepted June 25, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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