A new mechanism of anticancer drug: Analysis and identification of free radicals derived from podophyllotoxin related compounds in the presence of Cu (II)

Abstract

VP-16 is a clinical anticancer drug for the treatment of a number of human cancers. Anticancer activity of VP-16 has been suggested to be due to a covalent enzyme-DNA complex between the drug and type II topoisomerase or to involvement of free radical species, which in turn cause double-strand DNA breaks in cancer. Previously, we have found that hydroxyl radical (・OH)is generated during a redox-dependent complex formation between Cu(II) and VP-16 in the presence of molecular dioxygen (O₂), suggesting the ・OH participation in the single-and double-strand breaks of DNA. On the basis of results, we extended our investigation to look into the mechanism in detail, and VP-16 and its related compounds were found to form both organic free radical species and ・OH in the presence of Cu(II) as detected by ESR and spin-trapping methods, respectively, their structures being analyzed by computer simulation and molecular orbital calculation. Then, we examined the relationship between the free radical formations and DNA-cleaving activities, and proposed a new mechanism of the free radicals-dependent DNA cleavage.