β-拉帕醌和相关萘醌诱导 DNA 拓扑异构酶 II 介导的 DNA 切割。,Cancer Research

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β-拉帕醌和相关萘醌诱导 DNA 拓扑异构酶 II 介导的 DNA 切割。
Cancer Research ( IF 12.5 ) Pub Date : 1997-02-15
B Frydman ₁ , L J Marton , J S Sun , K Neder , D T Witiak , A A Liu , H M Wang , Y Mao , H Y Wu , M M Sanders , L F Liu

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最近的研究表明，3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) 抑制 DNA 拓扑异构酶 I 的机制不同于喜树碱。为研究β-拉帕醌的作用机制，合成了一系列β-拉帕醌和相关萘醌，并评估了它们对药物敏感和耐药细胞系和纯化的人类DNA拓扑异构酶的活性。与之前的报告一致，β-拉帕酮不会诱导拓扑异构酶 I 介导的 DNA 断裂。然而，β-拉帕醌和相关的萘醌，如甲萘醌，在纯化的人类 DNA 拓扑异构酶 IIalpha 存在下会诱导蛋白质连接的 DNA 断裂。β-lapachone 和相关萘醌对拓扑异构酶 IIalpha 的中毒与 ATP 无关，并且涉及可逆可裂解复合物的形成。甲萘醌（一种对醌）和β-拉帕醌（一种邻醌）之间的结构相似性，以及它们在拓扑异构酶 IIalpha 中毒方面的相似活性，表明这些醌的化学反应性具有共同的作用机制。事实上，这两种醌都与巯基乙醇形成加合物，而 β-拉帕酮的反应性高 10 倍。与硫醇形成加合物的速率与上述醌的拓扑异构酶 II 中毒活性之间存在明显的相关性。在初步研究中，发现β-拉帕醌和相关萘醌类对一组药物敏感和耐药的肿瘤细胞系具有细胞毒性，

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Induction of DNA topoisomerase II-mediated DNA cleavage by beta-lapachone and related naphthoquinones.

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.

更新日期：2019-11-01

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