The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells


DNA topoisomerases (topos) are the target of several drugs commonly
used in cancer chemotherapy; these drugs induce topo-DNA complexes with
either topo I or topo II that eventually trigger cell death. The
inhibition of these enzymes induces DNA alterations that may also lead
to carcinogenic effects; indeed, an increased risk for developing
leukemia has been observed in patients treated with some topo II
inhibitors. Several flavonoids have been shown to interact with
purified topo I and topo II, therefore suggesting that these compounds
may possess both anticancer and carcinogenic activity. Because the
activity of a drug on purified topoisomerases does not always represent
the activity in the cell, the aim of this work is to evaluate the
effects of several common dietary flavonoids on these enzymes in cells.
Using the cell-based TARDIS assay, we have evaluated the effects of the
flavonoids quercetin, apigenin, fisetin and myricetin on topo I and
topo II in K562 human leukemia cells at several concentrations and
exposure times. Quercetin and apigenin induced moderate levels of topo
II-DNA complexes and did not induce topo I-DNA complexes in these
cells. Fisetin induced neither topo I- nor topo II-DNA complexes, but
behaved as a catalytic inhibitor of both enzymes. Myricetin induced
high levels of topo-DNA complexes with both enzymes. In addition,
murine embryo fibroblasts lacking topo IIβ were resistant to
myricetin-induced cell-growth inhibition, therefore suggesting that
topo IIβ is an important drug target for this flavonoid. These results
support the idea that specific concentrations of some dietary
flavonoids may produce topoisomerase-mediated carcinogenic and
chemotherapeutic effects in vivo. The ability of myricetin to
induce topo-DNA complexes with both topo I and topo II in leukemia
cells may be therapeutically useful and deserves further study.