Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells

Phytomedicine. 2012 May 15;19(7):618-24. doi: 10.1016/j.phymed.2012.02.003. Epub 2012 Mar 6.

Abstract

DNA topoisomerases are nuclear enzymes that are the targets for several anticancer drugs. In this study we investigated the antiproliferative activity against human leukaemia cell lines and the effects on topoisomerase I and II of evodiamine, which is a quinazolinocarboline alkaloid isolated from the fruit of a traditional Chinese medicinal plant, Evodia rutaecarpa. We report here the anti-proliferative activity against human leukaemia cells K562, THP-1, CCRF-CEM and CCRF-CEM/C1 and the inhibitory mechanism on human topoisomerases I and II, important anti-cancer drugs targets, of evodiamine. Evodiamine failed to trap [Topo-DNA] complexes and induce any detectable DNA damage in cells, was unable to bind or intercalate DNA, and arrested cells in the G(2)/M phase. The results suggest evodiamine is a dual catalytic inhibitor of topoisomerases I and II, with IC(50) of 60.74 and 78.81 μM, respectively. The improved toxicity towards camptothecin resistant cells further supports its inhibitory mechanism which is different from camptothecin, and its therapeutic potential.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Damage
  • DNA Topoisomerases / metabolism*
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Drugs, Chinese Herbal / pharmacology
  • Drugs, Chinese Herbal / therapeutic use
  • Evodia / chemistry
  • Fruit
  • Humans
  • Inhibitory Concentration 50
  • Leukemia / drug therapy*
  • Phytotherapy*
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Topoisomerase I Inhibitors / pharmacology
  • Topoisomerase I Inhibitors / therapeutic use
  • Topoisomerase II Inhibitors / pharmacology
  • Topoisomerase II Inhibitors / therapeutic use
  • Topoisomerase Inhibitors / pharmacology
  • Topoisomerase Inhibitors / therapeutic use*

Substances

  • Antineoplastic Agents, Phytogenic
  • Drugs, Chinese Herbal
  • Quinazolines
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Topoisomerase Inhibitors
  • evodiamine
  • DNA Topoisomerases
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • Camptothecin