Antioxidants and trichostatin A synergistically protect against in vitro cytotoxicity of Ni2+ in human hepatoma cells.
The objective of this study was to investigate the separate and combined effects of antioxidants, trichostatin A (TSA) and their combination on the in vitro cytotoxicity of Ni2+ in human hepatoma cells. Cell viability, lactate dehydrogenase (LDH) release, and DNA fragmentation were measured as indicators of cell damage. Reactive oxygen species (ROS) generation and histone acetylation were also measured. The cytotoxicity of Ni2+ increased in a time- and dose-dependent manner. In the presence of 2 mM Ni2+, ROS generation increased 365% (p<0.05), while histone acetylation decreased 37% (p<0.05). Although antioxidants, ascorbic acid (AA, 0.5 or 1 mM), reduced glutathione (GSH, 100 or 200 microM) and N-acetyl-cysteine (NAC, 0.5 or 1 mM) strongly inhibited ROS generation, their effect on Ni2+-caused histone hypoacetylation was not so obvious. On the contrary, TSA (100 nM) showed no inhibition on ROS generation but significantly increased histone acetylation in both control and Ni2+-exposed cells. As expected, the combination of antioxidants and TSA possessed the activity of both diminishing ROS generation and increasing histone hypoacetylation caused by Ni2+. Further studies found that both antioxidants and TSA could diminish the cytotoxicity of Ni2+, and their combined effects obviously improved each of their protection roles, indicating that both ROS generation and histone hypoacetylation are involved in the cytotoxicity of Ni2+, and the combination of antioxidants and TSA may act as a useful strategy to protect against this cytotoxicity.
Kang
Jiuhong
J
School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China. kangjiuhong@lzu.edu.cn
Zhang
Dawei
D
Chen
Jie
J
Liu
Qing
Q
Lin
Changjun
C
D000107:Acetylation; D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008113:Liver Neoplasms; D009532:Nickel / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; C012589:trichostatin A; D009532:Nickel; D005978:Glutathione; D001205:Ascorbic Acid; D000111:Acetylcysteine