Induction of mammalian topoisomerase II dependent DNA cleavage by nonintercalative flavonoids, genistein and orobol

Biochem Pharmacol. 1990 Feb 15;39(4):737-44. doi: 10.1016/0006-2952(90)90153-c.


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.

Publication types

  • Comparative Study

MeSH terms

  • Amsacrine / pharmacology
  • Animals
  • Cattle
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / metabolism*
  • DNA, Bacterial / metabolism*
  • Enzyme Inhibitors*
  • Escherichia coli
  • Etoposide / pharmacology
  • Flavonoids / pharmacology*
  • Genistein
  • Humans
  • Intercalating Agents
  • Isoflavones / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship


  • DNA, Bacterial
  • Enzyme Inhibitors
  • Flavonoids
  • Intercalating Agents
  • Isoflavones
  • Amsacrine
  • Etoposide
  • Genistein
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • orobol