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J Biol Chem, Vol. 273, Issue 28, 17643-17650, July 10, 1998
From the Departments of Merbarone is a catalytic inhibitor of
topoisomerase II that is in clinical trials as an anticancer agent.
Despite the potential therapeutic value of this drug, the mechanism by
which it blocks topoisomerase II activity has not been delineated.
Therefore, to determine the mechanistic basis for the inhibitory action
of merbarone, the effects of this drug on individual steps of the catalytic cycle of human topoisomerase II
Merbarone Inhibits the Catalytic Activity of Human
Topoisomerase II
by Blocking DNA Cleavage
and¶
Biochemistry and
¶ Medicine (Oncology), Vanderbilt University School of Medicine,
Nashville, Tennessee 37232-0146
were assessed.
Concentrations of merbarone that inhibited catalytic activity 
80%
had no effect on either enzyme·DNA binding or ATP hydrolysis. In
contrast, the drug was a potent inhibitor of enzyme-mediated DNA
scission (in the absence or presence of ATP), and the inhibitory
profiles of merbarone for DNA cleavage and relaxation were similar.
These data indicate that merbarone acts primarily by blocking
topoisomerase II-mediated DNA cleavage. Merbarone inhibited DNA
scission in a global (rather than site-specific) fashion but did not
appear to intercalate into DNA or bind in the minor groove. Since the drug competed with etoposide (a cleavage-enhancing agent that binds
directly to topoisomerase II), it is proposed that merbarone exerts its
inhibitory effects through interactions with the enzyme and that the
drug shares an interaction domain on topoisomerase II with
cleavage-enhancing agents.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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