Institute for Health Research and Policy, London Metropolitan University, London, UK.
Phytomedicine. 2012 May 15;19(7):618-24. doi: 10.1016/j.phymed.2012.02.003. Epub 2012 Mar 6.
DNA topoisomerases are nuclear enzymes that are the targets for several anticancer drugs. In this study we investigated the antiproliferative activity against human leukaemia cell lines and the effects on topoisomerase I and II of evodiamine, which is a quinazolinocarboline alkaloid isolated from the fruit of a traditional Chinese medicinal plant, Evodia rutaecarpa. We report here the anti-proliferative activity against human leukaemia cells K562, THP-1, CCRF-CEM and CCRF-CEM/C1 and the inhibitory mechanism on human topoisomerases I and II, important anti-cancer drugs targets, of evodiamine. Evodiamine failed to trap [Topo-DNA] complexes and induce any detectable DNA damage in cells, was unable to bind or intercalate DNA, and arrested cells in the G(2)/M phase. The results suggest evodiamine is a dual catalytic inhibitor of topoisomerases I and II, with IC(50) of 60.74 and 78.81 μM, respectively. The improved toxicity towards camptothecin resistant cells further supports its inhibitory mechanism which is different from camptothecin, and its therapeutic potential.
DNA 拓扑异构酶是核酶，是几种抗癌药物的作用靶点。在这项研究中，我们研究了吴茱萸碱（一种从传统中药吴茱萸果实中分离出来的喹唑啉咔唑生物碱）对人白血病细胞系的增殖抑制活性及其对拓扑异构酶 I 和 II 的影响。我们在这里报告了吴茱萸碱对人白血病细胞 K562、THP-1、CCRF-CEM 和 CCRF-CEM/C1 的抗增殖活性，以及其对人拓扑异构酶 I 和 II 的抑制机制，拓扑异构酶 I 和 II 是重要的抗癌药物靶点。吴茱萸碱不能捕获[Topo-DNA]复合物，也不能在细胞中诱导任何可检测到的 DNA 损伤，不能与 DNA 结合或嵌入 DNA，也不能将细胞阻滞在 G2/M 期。结果表明，吴茱萸碱是拓扑异构酶 I 和 II 的双重催化抑制剂，IC50 分别为 60.74 和 78.81 μM。吴茱萸碱对喜树碱耐药细胞的毒性增加进一步支持了其与喜树碱不同的抑制机制，这也为其治疗潜力提供了支持。
