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.
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.
Pae
H O
HO
Department of Microbiology and Immunology, Medicinal Resources Research Center of Wonkwang University, 344-2 Shinyong-Dong, Iksan-Shi, Chonbuk 570-749, South Korea.
Oh
G S
GS
Choi
B M
BM
Seo
E A
EA
Oh
H
H
Shin
M K
MK
Kim
T H
TH
Kwon
T O
TO
Chung
H T
HT
D017209:Apoptosis / Q000187:drug effects*; D001203:Ascomycota / Q000737:chemistry*; D053148:Caspase 3; D020169:Caspases / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D017382:Reactive Oxygen Species / Q000009:adverse effects*; D014255:Trichothecenes / Q000494:pharmacology*
C440202:4-acetyl-12,13-epoxy-9-trichothecene-3,15-diol; D017382:Reactive Oxygen Species; D014255:Trichothecenes; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione