Induction of apoptosis by 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol from Isaria japonica Yasuda through intracellular reactive oxygen species formation and caspase-3 activation in human leukemia HL-60 cells

• Published in: Toxicology in vitro 2003-02, Vol.17 (1), p.49-57
• Main Authors: Pae, H.O, Oh, G.S, Choi, B.M, Seo, E.A, Oh, H, Shin, M.K, Kim, T.H, Kwon, T.O, Chung, H.T
• Format: Article
• Language: English
• Subjects: 4-Acetyl-12,13-epoxyl-9-trichothecene-3,15-diol; Apoptosis; Apoptosis - drug effects; Ascomycota - chemistry; Biological and medical sciences; Caspase 3; Caspases - pharmacology; Dose-Response Relationship, Drug; General pharmacology; Glutathione - metabolism; HL-60 Cells; Humans; Isaria japonica Yasuda; Medical sciences; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Reactive oxygen species; Reactive Oxygen Species - adverse effects; Trichothecene; Trichothecenes - pharmacology
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/S0887-2333(02)00097-8

Recently we have reported that the trichothecene mycotoxin 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol (AETD) from the fruiting bodies of Isaria japonica Yasuda is a potent inducer of apoptosis in human promyelocytic HL-60 cells. The present study aims to characterize the molecular events leading to AETD-induced apoptosis in HL-60 cells. The percentage of apoptotic cells (annexin-V-positive cell population) increased dose- and time-dependently after AETD exposure. Apoptosis of HL-60 cells by AETD was associated with the formation of intracellular reactive oxygen species (ROS), the depletion of intracellular glutathione (GSH) and the activation of caspase-3. Pretreating the cells with the antioxidant N-acetyl- l-cystein (NAC) and the caspase-3 inhibitor Z-DEVD-fmk abrogated AETD-induced apoptosis and caspase-3 activation. NAC blocked intracellular ROS formation and GSH depletion, but Z-DEVD-fmk did not. These results indicate that AETD induces apoptosis in HL-60 cells by causing intracellular ROS formation and GSH depletion followed by the downstream event of caspase-3 activation.