INDUCTION OF DNA TOPOISOMERASE II-MEDIATED DNA CLEAVAGE BY BETA-LAPACHONE AND RELATED NAPHTHOQUINONES

Recent studies have suggested that ydro-2,2-dimethyl-2H-naphtho[1,2-b] pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mec hanism distinct from that of camptothecin, To study the mechanism of a ction of beta-lapachone, a series of beta-lapachone and related naphth oquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as eva luated. Consistent with the previous report, beta-lapachone does not i nduce topoisomerase I-mediated DNA breaks, However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA br eaks in the presence of purified human DNA topoisomerase II alpha. Poi soning of topoisomerase II alpha by beta-lapachone and related naphtho quinones is independent of ATP and involves the formation of reversibl e cleavable complexes, The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with thei r similar activity in poisoning topoisomerase II alpha, suggests a com mon mechanism of action involving chemical reactivity of these quinone s, Indeed, both quinones form adducts with mercaptoethanol, and beta-l apachone is 10-fold more reactive, There is an apparent correlation be tween the rates of the adduct formation with thiols and of the topoiso merase II-poisoning activity of the aforementioned quinones, In prelim inary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tum or cell lines, including MDR1-overexpressing cell lines, camptothecin- resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cel l line.