TY - JOUR
T1 - Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells
AU - Dong, Guie
AU - Luo, Jia
AU - Kumar, Vijay
AU - Dong, Zheng
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Cisplatin nephrotoxicity
KW - Suberoylanilide hydroxamic acid
KW - Trichostatin A
UR - http://www.scopus.com/inward/record.url?scp=75149160568&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75149160568&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00410.2009
DO - 10.1152/ajprenal.00410.2009
M3 - Article
C2 - 19889954
AN - SCOPUS:75149160568
SN - 0363-6127
VL - 298
SP - F293-F300
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 2
ER -