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Salvicine triggers DNA double-strand breaks and apoptosis by GSH-depletion-driven H2O2 generation and topoisomerase II inhibition
Cai Y.-J.; Lu J.-J.; Zhu H.; Xie H.; Huang M.; Lin L.-P.; Zhang X.-W.; Ding J.
2008-09-01
Source PublicationFree Radical Biology and Medicine
ISSN08915849
Volume45Issue:5Pages:627-635
Abstract

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 HO generation and Topo II inhibition. Our data reveal that treatment with SAL results in a pronounced increase in intracellular HO 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 HO generation, indicating that SAL-mediated HO 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 HO generation may also trigger DNA DSBs via poisoning of Topo II. All these findings together suggest that GSH-depletion-driven HO generation and Topo II inhibition are both critical for SAL-induced DNA DSBs and apoptosis. © 2008 Elsevier Inc. All rights reserved.

KeywordDna Double-strand Breaks Free Radicals Glutathione H2o2 Salvicine Topoisomerase Ii
DOI10.1016/j.freeradbiomed.2008.05.017
URLView the original
Indexed BySCIE
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000258995200011
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Cited Times [WOS]:39   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
AffiliationShanghai Institute of Materia Medica, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Cai Y.-J.,Lu J.-J.,Zhu H.,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 Y.-J.,Lu J.-J.,Zhu H.,Xie H.,Huang M.,Lin L.-P.,Zhang X.-W.,&Ding J..(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 Y.-J.,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.
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