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Thursday, July 22, 2004 7:57:46 AM
Vol. 11, Issue 6, 2069-2083, June 2000
Histone Deacetylase Inhibitors Trigger a G2 Checkpoint in Normal Cells That Is Defective in Tumor Cells
Ling Qiu,* Andrew Burgess,* David P. Fairlie, Helen Leonard,* Peter G. Parsons,* and Brian G. Gabrielli*§
*Queensland Cancer Fund Laboratories, Queensland Institute of Medical Research, and Joint Experimental Oncology Program, Department of Pathology, University of Queensland, Brisbane, Queensland, Australia; and Centre for Drug Design and Development, University of Queensland, St. Lucia, Queensland, Australia
Important aspects of cell cycle regulation are the checkpoints, which respond to a variety of cellular stresses to inhibit cell cycle progression and act as protective mechanisms to ensure genomic integrity. An increasing number of tumor suppressors are being demonstrated to have roles in checkpoint mechanisms, implying that checkpoint dysfunction is likely to be a common feature of cancers. Here we report that histone deacetylase inhibitors, in particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle checkpoint response in normal human cells, and this checkpoint is defective in a range of tumor cell lines. Loss of this G2 checkpoint results in the tumor cells undergoing an aberrant mitosis resulting in fractured multinuclei and micronuclei and eventually cell death. This histone deacetylase inhibitor-sensitive checkpoint appears to be distinct from G2/M checkpoints activated by genotoxins and microtubule poisons and may be the human homologue of a yeast G2 checkpoint, which responds to aberrant histone acetylation states. Azelaic bishydroxamic acid may represent a new class of anticancer drugs with selective toxicity based on its ability to target a dysfunctional checkpoint mechanism in tumor cells.
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These authors contributed equally to this work.
§ Corresponding author: Department of Pathology, University of Queensland Medical School, Herston, Queensland 4006, Australia. E-mail address: briang@mailbox.uq.edu.au.
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