title: Synergistic killing of human leukemia cells by antioxidants and trichostatin A.
abstract: OBJECTIVE
  Antioxidants and trichostatin A (TSA) are promising anticancer drugs, and are capable of enhancing the neoplastic toxicity of other chemicals that exert anticancer activity via different mechanisms. Since antioxidants and TSA (the specific inhibitor of histone deacetylase) are believed to combat cancer via different mechanisms, we sought to determine whether combining them would improve their anticancer activity in human leukemia cells (HL-60).
  
  
  METHODS
  HL-60 cells were treated with antioxidants (ascorbic acid, AA and N-acetyl-cysteine, NAC), TSA or their combination, and cell proliferation arrest, lactate dehydrogenase (LDH) release and cell viability were measured as indicators of cell damage. Accumulation of reactive oxygen species (ROS) and the acetylation of histones were also measured.
  
  
  RESULTS
  The cytotoxicity of AA, NAC and TSA increased in a time- and dose-dependent manner. AA (1, 2 and 4 mM) and NAC (0.2, 0.5 and 1 mM) were able to diminish ROS generation but showed no influence on histone acetylation in HL-60 cells. In contrast, TSA (20, 50, 100 and 200 nM) did not inhibit ROS generation but significantly increased histone acetylation, indicating a possible role for both scavenging ROS and increasing histone acetylation in the induction of cell death in HL-60 cells. This conclusion was further confirmed by the finding that the combination of antioxidant and TSA not only diminished ROS generation, but also increased histone acetylation, and hence showed greater cytotoxicity in HL-60 cells than either component alone.
  
  
  CONCLUSIONS
  Our findings show that combining antioxidants and TSA can enhance their neoplastic toxicity at least in human leukemia HL-60 cells, providing a new approach to the design of chemotherapy strategies and the development of anticancer drugs.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou, China. kangjiuhong@lzu.edu.cn
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Kang
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Wanming
authors.initials: W
authors.lastname: Da
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Ou
mesh_terms: D000107:Acetylation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007938:Leukemia / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000032:analysis
chemical_list: D000975:Antioxidants; D006657:Histones; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; C012589:trichostatin A; D007770:L-Lactate Dehydrogenase