Induction of DNA topoisomerase II-mediated DNA cleavage by β-lapacphone and related naphthoquinones

Benjamin Frydman, Laurence J. Marton, Jerry S. Sun, Karen Neder, Donald T. Witiak, Angela A. Liu, Hui Min Wang, Yong Mao, Hong Yan Wu, Marilyn M. Sanders, Leroy-Fong Liu

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172 引文 斯高帕斯(Scopus)

摘要

Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H- naphtho[1,2-b]pyran-5,6-dione (β-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of β-lapachone, a series of β-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, β-lapachone does not induce topoisomerase I- mediated DNA breaks. However, β-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIα. Poisoning of topoisomerase IIα by β-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 β-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIα, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and β-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, β-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive tumor cell lines, including MDR1-overexpressing cell lines, camptothecin- resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.

原文英語
頁(從 - 到)620-627
頁數8
期刊Cancer Research
57
發行號4
出版狀態已發佈 - 1997
對外發佈Yes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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