Naringenin-induced apoptosis is attenuated by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human leukemia U937 cells.

Abstract

Naringenin, a naturally occurring citrus flavonone, has shown cytotoxicity in various human cancer cell lines as well as inhibitory effects on tumor growth and there is increasing interest in its therapeutic applications. In this study, the effect of ectopic Bcl-2 expression on naringenin-induced apoptosis was investigated. We found that Bcl-2 overexpression markedly protected human leukemia U937 cells from time- and dose-dependent induction of apoptosis by naringenin, as did caspase-3 and caspase-9 inhibitors. Additionally, Bcl-2 overexpression attenuated naringenin-induced Bax translocation and cytosolic release of cytochrome c. Our results also indicated that co-administration of HA14-1 and naringenin increased apoptosis in Bcl-2 overexpressing U937 cells by restoring mitochondrial dysfunction and activation of caspase-9 and caspase-3, as well as by cleavage of poly (ADP-ribose) polymerase. Taken together, these observations indicate that Bcl-2 confers apoptosis resistance to naringenin by inhibiting a mitochondrial amplification step in U937 cells.

• Authors: Cheng-Yun Jin, Cheol Park, Jun-Hyuk Lee, Kyung Tae Chung, Taeg Kyu Kwon, Gi-Young Kim, Byung Tae Choi, Yung Hyun Choi
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 23 Issue 2 Pg. 259-65 (Mar 2009) ISSN: 0887-2333 [Print] England
• PMID: 19124070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antioxidants
• Benzopyrans
• Caspase Inhibitors
• Drug Combinations
• Enzyme Inhibitors
• Estrogen Antagonists
• Flavanones
• Nitriles
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
• Cytochromes c
• naringenin

Topics

• Antineoplastic Agents (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Caspase Inhibitors
• Cell Survival (drug effects)
• Cytochromes c (metabolism)
• Cytosol (drug effects, enzymology)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Estrogen Antagonists (pharmacology)
• Flavanones (pharmacology)
• Humans
• Leukemia (drug therapy, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Nitriles (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• U937 Cells
• bcl-2-Associated X Protein (metabolism)