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Wu TS, Liao YC, Yu FY, Chang CH, Liu BH.
Mechanism of patulin-induced apoptosis in human leukemia cells (HL-60).
Toxicol Lett. 2008 Dec 15;183(1-3):105-11
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
Patulin (PAT) is a fungal secondary metabolite that exhibits
potential cellular and animal toxicities. In this study, human
promyelocytic leukemia (HL-60) cells were used to elucidate the
mechanism and death mode associated with PAT. Morphological
evidence of apoptosis, including membrane blebbing, nuclei
fragmentation and DNA laddering formation was clearly observed
6h after exposure to PAT. The results of Western blotting
indicated that PAT activated various processed caspases, and
cleaved DFF45 and poly (ADP-ribose) polymerase (PARP) in a
dose-dependent manner; it also induced a time-dependent increase
in caspase 3 and 9 catalytic activities. The apoptosis mediated
by PAT in HL-60 was accompanied with cytochrome c release from
mitochondria and Bcl-2 expression decrease. The presence of
thiol-containing compounds with PAT dramatically reduced the
caspase 3 activity that was triggered by PAT; the addition of
antioxidants, including mannitol and Tiron, had a similar
effect. However, the suppression of p53 protein expression by
RNA interference (RNAi) in human embryonic kidney (HEK293) cells
did not significantly modify PAT-elicited caspase 3 activity.
These findings suggest that PAT-induced apoptosis is mediated
through the mitochondrial pathway without the involvement of
p53; the interaction with sulfhydryl groups of macromolecules by
PAT and the subsequent generation of reactive oxygen species (ROS)
plays a primary role in the apoptotic process.
PMID: 18992795
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