Induction of mammalian topoisomerase II dependent DNA cleavage by nonintercalative flavonoids, genistein and orobol.
Two isoflavones, genistein (4',5,7-trihydroxyisoflavone) (1) and orobol (5,7,3',4'-tetrahydroxyisoflavone) (2) induced mammalian topoisomerase II dependent DNA cleavage in vitro. The cleavage activities of 1 and 2 were comparable to those of known antitumor agents with topoisomerase II dependent DNA cleavage activity such as 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP-16). Two flavones, fisetin (3,7,3',4'-tetrahydroxyflavone) (3) and quercetin (3,5,7,3',4'-pentahydroxyflavone) (4) showed topoisomerase II dependent DNA cleavage activity with similar potentials to that of Adriamycin. Addition of salt (0.5 M NaCl) to the reaction mixture containing genistein and topoisomerase II resulted in a great reduction of DNA cleavage, suggesting that the mechanism of the topoisomerase II dependent DNA cleavage induced by flavonoids is through the cleavable complex formation as seen with m-AMSA and VP-16. DNA unwinding assay using mammalian topoisomerase I showed that both 1 and 2 did not intercalate into DNA but both 3 and 4 intercalated like m-AMSA. Other structurally related flavonoids could not induce topoisomerase II dependent DNA cleavage, indicating that the restricted structures of flavonoids were required for the cleavage activity.
Yamashita
Y
Y
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Japan.
Kawada
S
S
Nakano
H
H
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism*; D004791:Enzyme Inhibitors; D004926:Escherichia coli; D005047:Etoposide / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D019833:Genistein; D006801:Humans; D007364:Intercalating Agents; D007529:Isoflavones / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007364:Intercalating Agents; D007529:Isoflavones; D000677:Amsacrine; D005047:Etoposide; D019833:Genistein; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C059811:orobol