LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation

doi:10.1038/aps.2009.131

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	LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation
	Zhou, Yu-bo; Feng, Xu; Wang, Li-na; Du, Jun-qing; Zhou, Yue-yang; Yu, Hai-ping; Zang, Yi; Li, Jing-ya; Li, Jia
刊名	ACTA PHARMACOLOGICA SINICA
	2009-09
卷号	30 期号:9 页码:1359-1368
关键词	LGH00031 ortho-quinone CDC25B irreversible inhibitor ROS
ISSN号	1671-4083
DOI	10.1038/aps.2009.131
文献子类	Article
英文摘要	Aim: To discover novel cell division cycle 25 (CDC25) B inhibitors and elucidate the mechanisms of inhibition in cancer cells. Methods: Cell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression and phosphorylation was examined by Western blot analysis. Results: LGH00031 inhibited CDC25B irreversibly in vitro in a dose-dependent manner, and impaired the proliferation of tumor cell lines. In synchronized HeLa cells, LGH00031 delayed the cell cycle progression at the G(2)/M phase. LGH00031 increased cyclin-dependent kinase 1 (CDK1) tyrosine 15 phosphorylation and cyclin B1 protein level. The activity of LGH00031 against CDC25B in vitro relied on the existence of 1,4-dithiothreitol (DTT) or dihydrolipoic acid and oxygen. The oxygen free radical scavenger catalase and superoxide dismutase reduced the inactivation of CDC25 by LGH00031, confirming that reactive oxygen species (ROS) mediate the inactivation process in vitro. LGH00031 accelerated cellular ROS production in a dose-dependent manner, and N-acetyl cysteine (NAC) markedly decreased the ROS production induced by LGH00031. Correspondingly, the LGH00031-induced decrease in cell viability and cell cycle arrest, cyclin B1 protein level, and phosphorylation of CDK1 tyrosine 15 were also rescued by NAC that decreased ROS production. Conclusion: The activity of LGH00031 at the molecular and cellular level is mediated by ROS.
资助项目	National Natural Science Foundation of China[30801405] ; Major State Hi-tech Research and Development Program[2006AA02Z315] ; Qi Ming Xing Foundation of Shanghai Ministry of Science and Technology[08QH14005]
WOS关键词	CDC25 PHOSPHATASES ; TRANSGENIC MICE ; IN-VIVO ; DISCOVERY ; ANALOGS ; SPECIFICITY ; MECHANISM
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:3672212
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000269894400019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279141]
专题	国家新药筛选中心药物安全性评价中心
通讯作者	Li, Jia
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Yu-bo,Feng, Xu,Wang, Li-na,et al. LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation[J]. ACTA PHARMACOLOGICA SINICA,2009,30(9):1359-1368.
APA	Zhou, Yu-bo.,Feng, Xu.,Wang, Li-na.,Du, Jun-qing.,Zhou, Yue-yang.,...&Li, Jia.(2009).LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation.ACTA PHARMACOLOGICA SINICA,30(9),1359-1368.
MLA	Zhou, Yu-bo,et al."LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation".ACTA PHARMACOLOGICA SINICA 30.9(2009):1359-1368.