G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation

doi:10.1038/aps.2014.105

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation
	He, Peng-xing 1; Zhang, Jie 3; Che, Yong-sheng 2; He, Qiao-jun 1; Chen, Yi3 ; Ding, Jian3
刊名	ACTA PHARMACOLOGICA SINICA
	2014-12
卷号	35 期号:12 页码:1546-1555
关键词	G226 epipolythiodioxopiperazine 11 '-deoxyverticillin A anti-cancer agent Topo II DNA damage apoptosis ROS antioxidant
ISSN号	1671-4083
DOI	10.1038/aps.2014.105
文献子类	Article
英文摘要	Aim: G226 is a novel derivative of epipolythiodioxopiperazines with potent inhibitory activity against cancer cells. Here, we sought to identify potential targets involved in the anti-cancer activity of G226. Methods: Cell proliferation assay was conducted in a panel of 12 human cancer cell lines. The activities of topoisomerase I (Topo I) and Topo II were studied using supercoiled pBR322 DNA relaxation and kDNA decatenation assays. ROS production was assessed with probes DCFH-DA and H&E. Western blot analysis and flow cytometry were used to examine DNA damage, apoptosis and cell cycle changes. Results: G226 displayed potent cytotoxicity in the 12 human cancer cell lines with a mean IC50 value of 92.7 nmol/L. This compound (1-100 mu mol/L) selectively inhibited the activity of Topo II, and elevated the expression of phosphorylated-H2AX in a dose-dependent manner. In Topo II-deficient HL60/MX2 cells, however, G226-induced DNA damage, apoptosis and cytotoxicity were only partially reduced, suggesting that Topo II was not essential for the anti-tumor effects of G226. Furthermore, G226 (0.125-2 mu mol/L) dose-dependently elevated the intracellular levels of H2O2 and O-2(radical) (anion) in the cancer cells, and pretreatment with GSH, NAC or DTT not only blocked G226-induced intracellular accumulation of ROS, but also abrogated G226-mediated phosphorylation of H2AX, apoptosis and cytotoxicity. Conclusion: G226-mediated ROS production contributes to the anti-cancer activity of this compound.
资助项目	National Natural Science Foundation of China[81273545] ; National Basic Research Program Grant of China[2013CB932503]
WOS关键词	DOUBLE-STRAND BREAKS ; TOPOISOMERASE-II ; OXIDATIVE STRESS ; INHIBITION ; SURVIVAL ; ARREST ; ROLES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5302618
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000345912300009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276814]
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	1.Zhejiang Univ, Sch Pharmaceut Sci, Inst Pharmacol & Toxicol, Hangzhou 310058, Zhejiang, Peoples R China; 2.Beijing Inst Pharmacol & Toxicol, Beijing 100190, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	He, Peng-xing,Zhang, Jie,Che, Yong-sheng,et al. G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation[J]. ACTA PHARMACOLOGICA SINICA,2014,35(12):1546-1555.
APA	He, Peng-xing,Zhang, Jie,Che, Yong-sheng,He, Qiao-jun,Chen, Yi,&Ding, Jian.(2014).G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation.ACTA PHARMACOLOGICA SINICA,35(12),1546-1555.
MLA	He, Peng-xing,et al."G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation".ACTA PHARMACOLOGICA SINICA 35.12(2014):1546-1555.