Document Detail


Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity.
MedLine Citation:
PMID:  17291459     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Recent work has suggested a role of p53 in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study determined the possible involvement of oxidative stress in p53 activation under the pathological condition using in vitro and in vivo models. In cultured renal proximal tubular cells, cisplatin at 20 microM induced an early p53 phosphorylation followed by protein accumulation. Cisplatin also induced reactive oxygen species (ROS), among which hydroxyl radicals showed a rapid and drastic accumulation. Dimethylthiourea (DMTU) and N-acetyl-cysteine (NAC) attenuated hydroxyl radical accumulation, and importantly, diminished p53 activation during cisplatin treatment. This was accompanied by the suppression of PUMA-alpha, a p53-regulated apoptotic gene. Concomitantly, mitochondrial cytochrome c release and apoptosis were ameliorated. Notably, DMTU and NAC, when added post-cisplatin treatment, were also inhibitory to p53 activation and apoptosis. In C57BL/6 mice, cisplatin at 30 mg/kg induced p53 phosphorylation and protein accumulation, which was also abrogated by DMTU. DMTU also ameliorated tissue damage, tubular cell apoptosis and cisplatin-induced renal failure. Collectively, this study has suggested a role of oxidative stress, particularly hydroxyl radicals, in cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity.
Authors:
Man Jiang; Qingqing Wei; Navjotsin Pabla; Guie Dong; Cong-Yi Wang; Tianxin Yang; Sylvia B Smith; Zheng Dong
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-01-07
Journal Detail:
Title:  Biochemical pharmacology     Volume:  73     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-03-27     Completed Date:  2007-05-17     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1499-510     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*,  physiology
Cells, Cultured
Cisplatin / pharmacology
Free Radical Scavengers / pharmacology*
Genes, p53 / physiology
Hydroxyl Radical / metabolism*
Kidney / drug effects*,  pathology
Kidney Tubules / drug effects*,  metabolism,  pathology
Male
Mice
Mice, Inbred C57BL
Rats
Reactive Oxygen Species
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
R01 DK067388/DK/NIDDK NIH HHS; R01 DK067388-02/DK/NIDDK NIH HHS; R01 DK087843/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Free Radical Scavengers; 0/Reactive Oxygen Species; 0/Tumor Suppressor Protein p53; 3352-57-6/Hydroxyl Radical; Q20Q21Q62J/Cisplatin
Comments/Corrections

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


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