Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells.
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 microM SAHA or 0.1 microM 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.
Dong
Guie
G
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912, USA.
Luo
Jia
J
Kumar
Vijay
V
Dong
Zheng
Z
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C012589:trichostatin A; D000077337:Vorinostat; D045304:Cytochromes c; D064447:Checkpoint Kinase 2; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin