title: Inhibitors of histone deacetylases enhance neurotoxicity of DNA damage.
abstract: The nonselective inhibitors of class I/II histone deacetylases (HDACs) including trichostatin A and the clinically used suberoylanilide hydroxamic acid (SAHA, vorinostat) are neuroprotective in several models of neuronal injury. Here, we report that in cultured cortical neurons from newborn rats and in the cerebral cortex of whole neonate rats, these HDAC inhibitors exacerbated cytotoxicity of the DNA double-strand break (DSB)-inducing anticancer drug etoposide by enhancing apoptosis. Similar neurotoxic interactions were also observed in neurons that were treated with other DNA damaging drugs including cisplatin and camptothecin. In addition, in rat neonates, SAHA increased cortical neuron apoptosis that was induced by a single injection of the NMDA receptor antagonist dizocilpine (MK801). In etoposide-treated neurons, the nonselective HDAC inhibition resulted in more DSBs. It also potentiated etoposide-induced accumulation and phosphorylation of the pro-apoptotic transcription factor p53. Moreover, nonselective HDAC inhibition exacerbated neuronal apoptosis that was induced by the overexpressed p53. Importantly, such effects cannot be fully explained by inhibition of HDAC1, which is known to play a role in DSB repair and regulation of p53. The specific HDAC1 inhibitor MS275 only moderately enhanced etoposide-induced neuronal death. Although in etoposide-treated neurons MS275 increased DSBs, it did not affect activation of p53. Our findings suggest that besides HDAC1, there are other class I/II HDACs that participate in neuronal DNA damage response attenuating neurotoxic consequences of genotoxic insults to the developing brain.
authors: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, 511 S. Floyd St., MDR616, Louisville, KY, 40292, USA.
authors: A
authors: A
authors: Vashishta
authors: M
authors: M
authors: Hetman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002166:Camptothecin / Q000633:toxicity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002945:Cisplatin / Q000633:toxicity; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000633:toxicity; D005047:Etoposide / Q000008:administration & dosage / Q000633:toxicity; D016158:Genes, p53; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007276:Injections, Intraventricular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C118739:entinostat; D000077337:Vorinostat; D016291:Dizocilpine Maleate; D005047:Etoposide; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1; D002945:Cisplatin; D002166:Camptothecin