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

Abstract
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.
AuthorsFei-Hong Chen, Lin-Bo Zhang, Lei Qiang, Zhen Yang, Tian Wu, Mei-Juan Zou, Lei Tao, Qi-Dong You, Zhi-Yu Li, Yong Yang, Qing-Long Guo
JournalCancer letters (Cancer Lett) Vol. 296 Issue 1 Pg. 96-105 (Oct 1 2010) ISSN: 1872-7980 [Electronic] Ireland
PMID20580989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Flavones
  • LYG 202
  • Piperazines
  • Reactive Oxygen Species
  • Adenosine Triphosphate
  • Matrix Metalloproteinases
  • Glutathione
Topics
  • Adenosine Triphosphate (metabolism)
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Fractionation
  • Cytosol (drug effects, metabolism)
  • Flavones (pharmacology)
  • Glutathione (metabolism)
  • Hep G2 Cells (drug effects, pathology)
  • Humans
  • Kinetics
  • Matrix Metalloproteinases (drug effects, metabolism)
  • Membrane Potentials (drug effects, physiology)
  • Mitochondria (drug effects, metabolism)
  • Mitochondrial Membranes (drug effects, physiology)
  • Piperazines (pharmacology)
  • Reactive Oxygen Species (metabolism)

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