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Vol. 60, Issue 4, 828-837, October 2001
Joint Experimental Oncology Program, Department of Pathology,
University of Queensland, Brisbane, Queensland (A.J.B., S.P., R.W.,
B.G.G.); Queensland Institute of Medical Research, Brisbane, Queensland
(T.J.P., P.G.P.); Garvan Institute of Medical Research, Cancer Research
Program, Darlinghurst, New South Wales (L.-J.K.H., E.A.M.); and Centre
for Immunology and Cancer Research, Princess Alexandra Hospital,
Brisbane, Queensland (N.S.), Australia
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.
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