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

• Published in: Phytomedicine (Stuttgart) Vol. 19; no. 7; pp. 618 - 624
• Main Authors: Pan, Xiaobei, Hartley, Janet M., Hartley, John A., White, Kenneth N., Wang, Zhengtao, Bligh, S.W. Annie
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 15-05-2012; Urban & Fischer Verlag
• Subjects: Alkaloids; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Antitumor agents; Camptothecin; Camptothecin - pharmacology; Catalytic inhibitor; Cell Line, Tumor; Cell Proliferation - drug effects; CPT-resistant; DNA Damage; DNA topoisomerase; DNA Topoisomerases - metabolism; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; Drug Resistance, Neoplasm - drug effects; Drug therapy; Drugs; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Enzymes; Evodia - chemistry; Evodia rutaecarpa; Evodiamine; Fruit; Fruits; Health aspects; Humans; Inhibitory Concentration 50; Leukemia; Leukemia - drug therapy; Medicinal plants; Medicine, Chinese; Phytotherapy; Quinazolines - pharmacology; Quinazolines - therapeutic use; Quinazolinocarboline; Quinolone; Topoisomerase; 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; Toxicity; CPT-resistant; Quinolone; m-AMSA; Topo I; DMSO; CPT; Quinazolinocarboline; MTT; Evodiamine; Sc; Topo II; Nck; Rel; Topoisomerase; Evodia rutaecarpa; Catalytic inhibitor; EtBr
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2012.02.003

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 G2/M phase. The results suggest evodiamine is a dual catalytic inhibitor of topoisomerases I and II, with IC50 of 60.74 and 78.81μM, respectively. The improved toxicity towards camptothecin resistant cells further supports its inhibitory mechanism which is different from camptothecin, and its therapeutic potential.