Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity

Man Jiang Livingston, QingQing Wei, Navjotsin Pabla, Guie Dong, Cong Yi Wang, Tianxin Yang, Sylvia B Smith, Zheng Dong

Research output: Contribution to journalArticle

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Abstract

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 μM 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-α, 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.

Original languageEnglish (US)
Pages (from-to)1499-1510
Number of pages12
JournalBiochemical Pharmacology
Volume73
Issue number9
DOIs
StatePublished - May 1 2007

Fingerprint

Scavenging
Hydroxyl Radical
Cisplatin
Chemical activation
Apoptosis
Acetylcysteine
Phosphorylation
Oxidative stress
Cysteine
Oxidative Stress
Kidney
Drug therapy
Cytochromes c
Inbred C57BL Mouse
Renal Insufficiency
Reactive Oxygen Species
Proteins
Genes
Tissue
Drug Therapy

Keywords

  • Apoptosis
  • Cisplatin
  • Hydroxyl radical
  • Nephrotoxicity
  • Oxidative stress
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. / Livingston, Man Jiang; Wei, QingQing; Pabla, Navjotsin; Dong, Guie; Wang, Cong Yi; Yang, Tianxin; Smith, Sylvia B; Dong, Zheng.

In: Biochemical Pharmacology, Vol. 73, No. 9, 01.05.2007, p. 1499-1510.

Research output: Contribution to journalArticle

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