Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation.

Abstract

Withaferin A, a major chemical constituent of Withania somnifera, has been reported for its tumor cell growth inhibitory activity, antitumor effects, and impairing metastasis and angiogenesis. The mechanism by which withaferin A initiates apoptosis remains poorly understood. In the present report, we investigated the effect of withaferin A on the apoptotic pathway in U937 human promonocytic cells. We show that withaferin A induces apoptosis in association with the activation of caspase-3. JNK and Akt signal pathways play crucial roles in withaferin A-induced apoptosis in U937 cells. Furthermore, we have shown that overexpression of Bcl-2 and active Akt (myr-Akt) in U937 cells inhibited the induction of apoptosis, activation of caspase-3, and PLC-gamma1 cleavage by withaferin A. Taken together, our results indicated that the JNK and Akt pathways and inhibition of NF-kappaB activity were key regulators of apoptosis in response to withaferin A in human leukemia U937 cells.

• Authors: Jung Hwa Oh, Tae-Jin Lee, Sang Hyun Kim, Yung Hyun Choi, Sang Han Lee, Jin Man Lee, Young-Ho Kim, Jong-Wook Park, Taeg Kyu Kwon
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 13 Issue 12 Pg. 1494-504 (Dec 2008) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19002588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caspase Inhibitors
• Enzyme Inhibitors
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Withanolides
• Cytochromes c
• Proto-Oncogene Proteins c-akt
• JNK Mitogen-Activated Protein Kinases
• Caspase 3
• Matrix Metalloproteinases
• withaferin A
• Ergosterol

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase Inhibitors
• Cell Line, Tumor (drug effects)
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• Down-Regulation
• Enzyme Inhibitors (metabolism)
• Ergosterol (analogs & derivatives, pharmacology)
• Humans
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• Leukemia (metabolism)
• Matrix Metalloproteinases (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Withanolides