Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells

Guie Dong, Jia Luo, Vijay Kumar, Zheng Dong

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), are emerging anticancer agents. In the current study, we examined the cytoprotective effects of these agents. Cisplatin induced 40-50% apoptosis in rat kidney proximal tubular cells in 18 h, which was suppressed to 20-30% by 1-5 μM SAHA or 0.1 μM TSA. Consistently, SAHA partially prevented cisplatin-induced caspase activation. The cytoprotective effects of SAHA and TSA were associated with long-term cell survival. During cisplatin treatment, Bax translocated to mitochondria, leading to cytochrome c release. Both Bax translocation and cytochrome c release were ameliorated by SAHA. Mechanistically, SAHA inhibited and TSA delayed p53 phosphorylation, acetylation, and activation during cisplatin incubation. At the upstream signaling level, SAHA blocked cisplatin-induced phosphorylation of Chk2, a key DNA damage response kinase. Interestingly, in HCT116 colon cancer cells, SAHA suppressed cisplatin-induced p53 activation, but enhanced apoptosis. The results suggest that inhibitors of histone deacetylases can protect against cisplatin nephrotoxicity by attenuating DNA damage response and associated p53 activation.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Histone Deacetylases
Cisplatin
trichostatin A
Apoptosis
Kidney
Cytochromes c
DNA Damage
Phosphorylation
vorinostat
Acetylation
Caspases
Antineoplastic Agents
Colonic Neoplasms
Cell Survival
Mitochondria
Phosphotransferases

Keywords

  • Cisplatin nephrotoxicity
  • Suberoylanilide hydroxamic acid
  • Trichostatin A

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells. / Dong, Guie; Luo, Jia; Kumar, Vijay; Dong, Zheng.

In: American Journal of Physiology - Renal Physiology, Vol. 298, No. 2, 01.02.2010.

Research output: Contribution to journalArticle

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