Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Free Radic Biol Med. 2017 Dec;113:406-412. doi: 10.1016/j.freeradbiomed.2017.10.377. Epub 2017 Oct 24.
Topotecan, a derivative of camptothecin, is an important anticancer drug for the treatment of various human cancers in the clinic. While the principal mechanism of tumor cell killing by topotecan is due to its interactions with topoisomerase I, other mechanisms, e.g., oxidative stress induced by reactive free radicals, have also been proposed. However, very little is known about how topotecan induces free radical-dependent oxidative stress in tumor cells. In this report we describe the formation of a topotecan radical, catalyzed by a peroxidase-hydrogen peroxide system. While this topotecan radical did not undergo oxidation-reduction with molecular O, it rapidly reacted with reduced glutathione and cysteine, regenerating topotecan and forming the corresponding glutathiyl and cysteinyl radicals. Ascorbic acid, which produces hydrogen peroxide in tumor cells, significantly increased topotecan cytotoxicity in MCF-7 tumor cells. The presence of ascorbic acid also increased both topoisomerase I-dependent topotecan-induced DNA cleavage complex formation and topotecan-induced DNA double-strand breaks, suggesting that ascorbic acid participated in enhancing DNA damage induced by topotecan and that the enhanced DNA damage is responsible for the synergistic interactions of topotecan and ascorbic acid. Cell death by topotecan and the combination of topotecan and ascorbic acid was predominantly due to necrosis of MCF-7 breast tumor cells.
拓扑替康是喜树碱的衍生物，是临床上治疗多种人类癌症的重要抗癌药物。虽然拓扑替康杀伤肿瘤细胞的主要机制是与拓扑异构酶 I 相互作用，但也提出了其他机制，例如活性自由基引起的氧化应激。然而，关于拓扑替康如何诱导肿瘤细胞中自由基依赖性氧化应激，人们知之甚少。在本报告中，我们描述了过氧化物酶-过氧化氢系统催化的拓扑替康自由基的形成。虽然这种拓扑替康自由基不能与分子 O 发生氧化还原反应，但它能迅速与还原型谷胱甘肽和半胱氨酸反应，再生拓扑替康并形成相应的谷胱甘肽和半胱氨酸自由基。在肿瘤细胞中产生过氧化氢的抗坏血酸显著增加了 MCF-7 肿瘤细胞中拓扑替康的细胞毒性。抗坏血酸的存在还增加了拓扑异构酶 I 依赖性拓扑替康诱导的 DNA 断裂复合物的形成和拓扑替康诱导的 DNA 双链断裂，表明抗坏血酸参与增强拓扑替康诱导的 DNA 损伤，并且增强的 DNA 损伤是拓扑替康和抗坏血酸协同作用的原因。拓扑替康和拓扑替康与抗坏血酸联合引起的细胞死亡主要是由于 MCF-7 乳腺癌细胞的坏死。
