title: Induction of DNA topoisomerase II-mediated DNA cleavage by beta-lapachone and related naphthoquinones.
abstract: Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of beta-lapachone, a series of beta-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, beta-lapachone does not induce topoisomerase I-mediated DNA breaks. However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIalpha. Poisoning of topoisomerase IIalpha by beta-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIalpha, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and beta-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.
authors.affiliation: Medical School, Division of Medicinal Chemistry, School of Pharmacy, University of Wisconsin-Madison, 53706, USA.
authors.forename: B
authors.initials: B
authors.lastname: Frydman
authors.forename: L J
authors.initials: LJ
authors.lastname: Marton
authors.forename: J S
authors.initials: JS
authors.lastname: Sun
authors.forename: K
authors.initials: K
authors.lastname: Neder
authors.forename: D T
authors.initials: DT
authors.lastname: Witiak
authors.forename: A A
authors.initials: AA
authors.lastname: Liu
authors.forename: H M
authors.initials: HM
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.forename: H Y
authors.initials: HY
authors.lastname: Wu
authors.forename: M M
authors.initials: MM
authors.lastname: Sanders
authors.forename: L F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008623:Mercaptoethanol / Q000378:metabolism; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014812:Vitamin K / Q000378:metabolism / Q000494:pharmacology*; D015003:Yeasts / Q000187:drug effects / Q000201:enzymology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009285:Naphthoquinones; D018894:Reverse Transcriptase Inhibitors; D059004:Topoisomerase I Inhibitors; D014812:Vitamin K; D008623:Mercaptoethanol; C014638:beta-lapachone; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin