Synergistic killing of human leukemia cells by antioxidants and trichostatin A.
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.
Kang
Jiuhong
J
School of Life Sciences, Lanzhou University, Lanzhou, China. kangjiuhong@lzu.edu.cn
Chen
Jie
J
Zhang
Dawei
D
Da
Wanming
W
Ou
Yingxian
Y
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
D000975:Antioxidants; D006657:Histones; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; C012589:trichostatin A; D007770:L-Lactate Dehydrogenase