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Lookup NU author(s): Dr Miguel Lopez-Lazaro,
Dr Elaine WillmoreORCiD,
Professor Caroline AustinORCiD
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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 11 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 11 inhibitors. Several flavonoids have been shown to interact with purified topo I and topo 11, 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 11 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 II beta were resistant to myricetin-induced cell-growth inhibition, therefore suggesting that topo II beta 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. (C) 2009 Elsevier B.V. All rights reserved.
Author(s): Lopez-Lazaro M, Willmore E, Austin CA
Publication type: Article
Publication status: Published
Journal: Mutation Research - Genetic Toxicology and Environmental Mutagenesis
Print publication date: 01/02/2010
ISSN (print): 1383-5718
ISSN (electronic): 1568-7864
Publisher: Elsevier BV
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