کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1910840 | 1046789 | 2008 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition
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کلمات کلیدی
GSHdl-buthionine-[S,R]-sulfoximineSalvicine2,7-dichlorofluoresceinkDNABSODCFH2-DANACDPICATATZSRBDSBDcf2,7-dichlorodihydrofluorescein diacetate - 2،7-dichlorodihydrofluorescein diacetate3-amino-1,2,4-triazole - 3-آمینو-1،2،4-تریاازولKinetoplast DNA - DNA کینتوپلاستMTT - MTTN-acetylcysteine - N-استیل سیستئینROS - ROSSAL - WILLdiphenyleneiodonium chloride - دی فینیلنیدونیم کلریدSOD - سدSuperoxide dismutase - سوکسوکس دیسموتازdouble-strand break - شکست دو ردیفHydroethidine - هیدروتیدینCatalase - کاتالازGlutathione - گلوتاتیونReactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 45, Issue 5, 1 September 2008, Pages 627-635
Journal: Free Radical Biology and Medicine - Volume 45, Issue 5, 1 September 2008, Pages 627-635
نویسندگان
Yu-Jun Cai, Jin-Jian Lu, Hong Zhu, Hua Xie, Min Huang, Li-Ping Lin, Xiong-Wen Zhang, Jian Ding,