The polyphenolic ellagitannin vescalagin acts as a preferential catalytic inhibitor of the α isoform of human DNA topoisomerase II
Mol Pharmacol. 2012-04-23; 82(1): 134-141
DOI: 10.1124/mol.111.077537
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Polyphenolic ellagitannins are natural compounds that are often associated with
the therapeutic activity of plant extracts used in traditional medicine. They
display cancer-preventing activity in animal models by a mechanism that remains
unclear. Potential targets have been proposed, including DNA topoisomerases II
(Top2). Top2α and Top2β, the two isoforms of the human Top2, play a crucial role
in the regulation of replication, transcription, and chromosome segregation. They
are the target of anticancer agents used in the clinic such as anthracyclines
(e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown
that the antitumor activity of etoposide was due primarily to the inhibition of
Top2α, whereas inhibition of Top2β was responsible for the development of
secondary malignancies, pointing to the need for more selective Top2α inhibitors.
Here, we show that the polyphenolic ellagitannin vescalagin preferentially
inhibits the decatenation activity of Top2α in vitro, by a redox-independent
mechanism. In CEM cells, we also show that transient small interfering
RNA-mediated down-regulation of Top2α but not of Top2β conferred a resistance to
vescalagin, indicating that the α isoform is a preferential target. We further
confirmed that Top2α inhibition was due to a catalytic inhibition of the enzyme
because it did not induce DNA double-strand breaks in CEM-treated cells but
prevented the formation of Top2α- rather than Top2β-DNA covalent complexes
induced by etoposide. To our knowledge, vescalagin is the first example of a
catalytic inhibitor for which cytotoxicity is due, at least in part, to the
preferential inhibition of Top2α.