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Vol. 11, Issue 6, 2069-2083, June 2000
*Queensland Cancer Fund Laboratories, Queensland Institute of
Medical Research, and Joint Experimental Oncology Program, Department
of Pathology, University of Queensland, Brisbane, Queensland,
Australia; and 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.
Centre for Drug Design and Development,
University of Queensland, St. Lucia, Queensland, Australia
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{at}mailbox.uq.edu.au.
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