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 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.
Chen
Fei-Hong
FH
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Zhang
Lin-Bo
LB
Qiang
Lei
L
Yang
Zhen
Z
Wu
Tian
T
Zou
Mei-Juan
MJ
Tao
Lei
L
You
Qi-Dong
QD
Li
Zhi-Yu
ZY
Yang
Yong
Y
Guo
Qing-Long
QL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002458:Cell Fractionation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000970:Antineoplastic Agents; D047309:Flavones; C541987:LYG 202; D010879:Piperazines; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D020782:Matrix Metalloproteinases; D005978:Glutathione