Cells lacking DNA topoisomerase II beta are resistant to genistein.
Evidence suggests that DNA topoisomerases (topos) may be involved in the anticancer and carcinogenic properties attributed to flavonoids. Using the cell-based assay TARDIS, the dietary flavonoids genistein (1) and luteolin (2) have been evaluated as topo I and topo II poisons and catalytic inhibitors in K562 leukemia cells. Both flavonoids induced topo II-DNA complexes, but they did not induce significant levels of topo I-DNA complexes. Genistein decreased the topo II-DNA complexes induced by the topo II poison etoposide, suggestive of a catalytic inhibition of topo II, and luteolin decreased the topo I-DNA complexes induced by the topo I poison camptothecin, indicative of a catalytic inhibition of topo I. Murine transgenic cells lacking topo II beta were resistant to genistein-induced cell growth inhibition (XTT assays) and cytotoxicity (clonogenic assay). High levels of topo II beta-DNA complexes were also observed in K562 cells exposed to genistein. These data suggest that topo II beta has an important function in genistein-induced cell growth inhibition and cell death. The possible role of topoisomerases in the putative anticancer and carcinogenic properties of genistein and luteolin is discussed.
López-Lazaro
Miguel
M
Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE2 4HH, United Kingdom.
Willmore
Elaine
E
Austin
Caroline A
CA
D000818:Animals; D004247:DNA / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000172:deficiency / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000172:deficiency* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D019833:Genistein / Q000494:pharmacology*; D047311:Luteolin / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure
D004268:DNA-Binding Proteins; D004247:DNA; D019833:Genistein; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D047311:Luteolin