Caspase-8 preferentially senses the apoptosis-inducing action of NG-18, a Gambogic acid derivative, in human leukemia HL-60 cells.

Abstract

Gambogic acid (GA) is the major active ingredient of gamboge secreted from a Chinese traditional medicine Garcinia hanburryi possessing potent anti-tumor activity. N-(2-ethoxyethyl)gambogamide (NG-18), a derivative of GA, also efficiently inhibits proliferation of cultured human tumor cells. The inhibition effect of NG-18 is associated with its ability to induce apoptosis. In the present study, NG-18 markedly induced leukemia HL-60 cells apoptosis, and the extrinsic and intrinsic apoptosis pathways were activated almost at the same time. NG-18-induced tumor cell apoptosis was associated with up-regulation of pro-apoptotic Bcl-2 family member Bax, and downregulation of anti-apoptotic protein Bcl-2. The NG-18-induced apoptosis was blocked completely by a pan-caspase inhibitor Z-VAD-FMK, indicating that caspases were functionally and actively involved in this process. The specific inhibition of caspase-8 activity using Z-IETD-FMK significantly blocked NG-18-induced apoptosis. In contrast, inhibition of other initiator caspases, caspase-2 or -9, using Z-VDVAD-FMK or Z-LEHD-FMK respectively had no effect on NG-18-induced apoptosis. Altogether, our data demonstrated that NG-18-induced apoptosis was dependent on caspases and caspase-8 acted as a key executor in the event.

• Authors: Zhijian Tao, Yunlong Zhou, Jinjian Lu, Wenhu Duan, Yuxin Qin, Xinxia He, Liping Lin, Jian Ding
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 5 Pg. 691-6 (May 2007) ISSN: 1555-8576 [Electronic] United States
• PMID: 17426447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drugs, Chinese Herbal
• N-(2-ethoxyethyl)gambogamide
• Proto-Oncogene Proteins c-bcl-2
• Xanthones
• bcl-X Protein
• Cytochromes c
• Poly(ADP-ribose) Polymerases
• Caspase 8

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 8 (metabolism)
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• Drugs, Chinese Herbal (pharmacology)
• Flow Cytometry
• Garcinia (chemistry)
• HL-60 Cells (drug effects, enzymology, pathology)
• Humans
• Molecular Structure
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Xanthones (chemistry, pharmacology)
• bcl-X Protein (metabolism)