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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. cisplatin nephrotoxicity suberoylanilide hydroxamic acid trichostatin A Copyright © 2010 the American Physiological Society
AJP - Renal Physiology – The American Physiological Society
Published: Feb 1, 2010
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