Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition
文献类型：期刊论文
| 作者 | Cai, Yu-Jun; Lu, Jin-Jian; Zhu, Hong; Xie, Hua ; Huang, Min; Lin, Li-Ping; Zhang, Xiong-Wen; Ding, Jian
|
| 刊名 | FREE RADICAL BIOLOGY AND MEDICINE
 |
| 出版日期 | 2008-09-01 |
| 卷号 | 45期号:5页码:627-635 |
| 关键词 | salvicine glutathione H2O2 topoisomerase II DNA double-strand breaks free radicals |
| ISSN号 | 0891-5849 |
| DOI | 10.1016/j.freeradbiomed.2008.05.017 |
| 文献子类 | Article |
| 英文摘要 | 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 11) 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 di-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 I 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. (c) 2008 Elsevier Inc. All rights reserved. |
| WOS关键词 | HL-60 CELL APOPTOSIS ; OXIDATIVE STRESS ; MEDIATED APOPTOSIS ; GLUTATHIONE DEPLETION ; GENE-EXPRESSION ; DOWN-REGULATION ; CANCER-CELLS ; COMET ASSAY ; ACTIVATION ; DAMAGE |
| 资助项目 | National Natural Sciences Foundation of China[30721005] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:000258995200011 |
| 出版者 | ELSEVIER SCIENCE INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272820]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian |
| 作者单位 | Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cai, Yu-Jun,Lu, Jin-Jian,Zhu, Hong,et al. Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition[J]. FREE RADICAL BIOLOGY AND MEDICINE,2008,45(5):627-635. |
| APA | Cai, Yu-Jun.,Lu, Jin-Jian.,Zhu, Hong.,Xie, Hua.,Huang, Min.,...&Ding, Jian.(2008).Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition.FREE RADICAL BIOLOGY AND MEDICINE,45(5),627-635. |
| MLA | Cai, Yu-Jun,et al."Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition".FREE RADICAL BIOLOGY AND MEDICINE 45.5(2008):627-635. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。