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| Salvicine 通过损耗谷胱甘肽-产生过氧化氢和抑制拓扑异构酶 II触发DNA双链断裂和细胞凋亡 |
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| Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition |
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| Cai Y.-J., Lu J.-J., Zhu H., Xie H., Huang M., Lin L.-P., Zhang X.-W., Ding J. 2009/5/29 18:38:57 |
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Free Radical Biology and Medicine, 2008, Volume 45, Issue 5
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| Glutathione (GSH), as the major small-molecule antioxidant in cells, has been implicated in the regulation of cell proliferation and apoptosis. Salvicine (SAL), a novel diterpenoid quinone compound, exhibits potent antitumor activities both in vitro and in vivo by poisoning topoisomerase II (Topo II) and has entered Phase II clinical trials for cancer therapy. Herein, we provide further evidence that SAL-induced DNA double-strand breaks (DSBs) and apoptosis by GSH depletion drives H2O2 generation and Topo II inhibition. Our data reveal that treatment with SAL results in a pronounced increase in intracellular H2O2 and is accompanied by the occurrence of DNA DSBs and apoptosis in epithelial HeLa cells. Furthermore, SAL was also noted to trigger a dramatic depletion of intracellular GSH via its direct reaction with GSH. Importantly, the introduction of GSH and overexpression of catalase antagonized SAL-mediated DNA DSBs and apoptosis, and the GSH synthesis inhibitor dl-buthionine-[S,R]-sulfoximine reduced SAL-mediated H2O2 generation, indicating that SAL-mediated H2O2 generation is derived from intracellular GSH depletion. Notably, SAL-mediated Topo II inhibition was also concentration-dependently reversed by GSH. Furthermore, we found that Topo II-defective HL-60/MX2 cells were almost completely resistant to SAL-induced DNA DSBs, suggesting that, in addition to its direct inhibitory effect on Topo II, SAL-mediated H2O2 generation may also trigger DNA DSBs via poisoning of Topo II. All these findings together suggest that GSH-depletion-driven H2O2 generation and Topo II inhibition are both critical for SAL-induced DNA DSBs and apoptosis. © 2008 Elsevier Inc. All rights reserved. |
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| Correspondence Address: Ding, J.; Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China; email: jding@mail.shcnc.ac.cn |
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 疾病资源中心
摘自：《西氏内科学》，第23版
患者女性，21岁，因干咳、间歇性气促2个月到急诊科就诊。开始症状为上呼吸道感染引起的鼻塞、流涕和咳嗽。医生检查后开了抗生素。服药后鼻部症状缓解，但仍有轻微干咳和呼吸困难。其他症状包括疲劳和焦虑。否认发热、体重减轻、胸痛、端坐呼吸、气喘、鼻后滴漏、胃灼热以及神经系统症状。
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