Document Detail


LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation.
MedLine Citation:
PMID:  19730430     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yu-bo Zhou; Xu Feng; Li-na Wang; Jun-qing Du; Yue-yang Zhou; Hai-ping Yu; Yi Zang; Jing-ya Li; Jia Li
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  30     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-04     Completed Date:  2009-11-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1359-68     Citation Subset:  IM    
Affiliation:
National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Blotting, Western
Dose-Response Relationship, Drug
Flow Cytometry
Hela Cells / drug effects
Humans
Quinones / pharmacology*
Reactive Oxygen Species / metabolism*
cdc25 Phosphatases / antagonists & inhibitors*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/LGH00031; 0/Quinones; 0/Reactive Oxygen Species; EC 3.1.3.16/CDC25B protein, human; EC 3.1.3.48/cdc25 Phosphatases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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