Reactive oxygen species-mitochondria pathway involved in LYG-202-induced apoptosis in human hepatocellular carcinoma HepG(2) cells

Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen spe...

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Bibliographic Details
Published in:Cancer letters 2010-10, Vol.296 (1), p.96
Main Authors: Chen, Fei-Hong, Zhang, Lin-Bo, Qiang, Lei, Yang, Zhen, Wu, Tian, Zou, Mei-Juan, Tao, Lei, You, Qi-Dong, Li, Zhi-Yu, Yang, Yong, Guo, Qing-Long
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Blotting, Western
Cell Fractionation
Cytosol - drug effects
Cytosol - metabolism
Flavones - pharmacology
Glutathione - metabolism
Hep G2 Cells - drug effects
Hep G2 Cells - pathology
Humans
Kinetics
Matrix Metalloproteinases - drug effects
Matrix Metalloproteinases - metabolism
Membrane Potentials - drug effects
Membrane Potentials - physiology
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Membranes - drug effects
Mitochondrial Membranes - physiology
Piperazines - pharmacology
Reactive Oxygen Species - metabolism
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Summary:Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen species (ROS) production and the downstream signaling pathway in the apoptosis of human hepatocellular carcinoma HepG(2) cells. Pretreatment with NAC (N-acetylcysteine), a ROS production inhibitor, partly inhibited the apoptosis induced by LYG-202 via blocking the ROS generation. Further data revealed that LYG-202 induced ROS accumulation followed by a decrease in mitochondrial membrane potential (MMP), release of cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) to cytosol, which induced apoptosis of the cells. Moreover, the mitogen-activated protein kinases (MAPK), the downstream effect of ROS accumulation including c-Jun N-terminal kinase (JNK) and p38 MAPK, could be activated by LYG-202. Taken together, the generation of ROS might play an important role in LYG-202-induced mitochondrial apoptosis pathway, which provided further support for LYG-202 as a novel anticancer therapeutic candidate.
ISSN:1872-7980
DOI:10.1016/j.canlet.2010.04.004