Apoptosis induced by a new flavonoid in human hepatoma HepG2 cells involves reactive oxygen species-mediated mitochondrial dysfunction and MAPK activation.

Abstract

Earlier reports suggest that protoapigenone showed remarkable anticancer activities. In the present study, the cytotoxic effect of a new flavonoid, 2-(cis-1, 2-dihydroxy 4-oxo-cyclohex-5-enyl)-5, 7-dihydroxy-chromone (DEDC), which is a protoapigenone analog, was investigated in human hepatoma HepG2 cells. We found that hepatoma cells were highly susceptible to DEDC in contrast with normal cells. The sustainable and rapid generation of reactive oxygen species was observed in DEDC-induced cell death. Following oxidative stress, DEDC sequentially decreased mitochondrial membrane potential (ΔΨm), reduced Bcl-2 expression, increased cytochrome c release, and activated caspase-3, -8, and -9. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK) was stimulated by treatment with DEDC. To further investigate the mechanisms of the DEDC-induced cell death, we examined the effects of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) and selective inhibitors for MAPK pathways on the cell death. The DEDC-induced cell death was significantly inhibited by both NAC and JNK inhibitor SP600125, but promoted by p38 MAPK inhibitor, SB203580. Together, DEDC may have antitumor effects in HepG2 cells through reactive oxygen species production as well as activation of MAPK signaling pathways.

• Authors: Huibin Liu, Yuling Xiao, Chaomei Xiong, Anhua Wei, Jinlan Ruan
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 654 Issue 3 Pg. 209-16 (Mar 11 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21241688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• 2-(cis-1,2-dihydroxy 4-oxo-cyclohex-5-enyl)-5,7-dihydroxychromone
• Anthracenes
• Cyclohexanones
• Flavones
• Imidazoles
• Pyridines
• Reactive Oxygen Species
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspases
• SB 203580
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Anthracenes (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (pathology)
• Caspases (metabolism)
• Cell Survival (drug effects)
• Cyclohexanones (pharmacology)
• Enzyme Activation (drug effects)
• Flavones (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Imidazoles (pharmacology)
• Intracellular Space (drug effects, metabolism)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Liver Neoplasms (pathology)
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation (drug effects)
• Pyridines (pharmacology)
• Reactive Oxygen Species (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)