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HU-331 and Oxidized Cannabidiol Act as Inhibitors of Human Topoisomerase IIα and β
journal contribution
posted on 2017-12-22, 00:00 authored by James
T. Wilson, Cole A. Fief, Klarissa D. Jackson, Susan L. Mercer, Joseph E. DeweeseTopoisomerase
II is a critical enzyme in replication, transcription,
and the regulation of chromatin topology. Several anticancer agents
target topoisomerases in order to disrupt cell growth. Cannabidiol
is a major non-euphoriant, pharmacologically active component of cannabis.
Previously, we examined the cannabidiol derivative HU-331 in order
to characterize the mechanism of the compound against topoisomerase
IIα. In this current work, we explore whether cannabidiol (CBD)
impacts topoisomerase II activity, and we additionally examine the
activity of these compounds against topoisomerase IIβ. CBD does
not appear to strongly inhibit DNA relaxation and is not a poison
of topoisomerase II DNA cleavage. However, oxidation of CBD allows
this compound to inhibit DNA relaxation by topoisomerase IIα
and β without poisoning DNA cleavage. Additionally, we found
that oxidized CBD, similar to HU-331, inhibits ATP hydrolysis and
can result in inactivation of topoisomerase IIα and β.
We also determined that oxidized CBD and HU-331 are both able to stabilize
the N-terminal clamp of topoisomerase II. Taken together, we conclude
that while CBD does not have significant activity against topoisomerase
II, both oxidized CBD and HU-331 are active against both isoforms
of topoisomerase II. We hypothesize that oxidized CBD and HU-331 act
against the enzyme through interaction with the N-terminal ATPase
domain. According to the model we propose, topoisomerase II inactivation
may result from a decrease in the ability of the enzyme to bind to
DNA when the compound is bound to the N-terminus.
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topoisomerase II inactivationSeveral anticancer agents target topoisomerasestopoisomerase II α.N-terminal ATPase domaintopoisomerase IIpoisoning DNA cleavagetopoisomerase II αHU -331 acttopoisomerase II β. CBDOxidized Cannabidiol ActHU -331DNA relaxationHuman Topoisomerase II αtopoisomerase II DNA cleavageimpacts topoisomerase II activityβ Topoisomerase II
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