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Open Access Highly Accessed Research article

Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells

Sung-Hee Cho1, Kyung-Sook Chung13, Jung-Hye Choi2, Dong-Hyun Kim1 and Kyung-Tae Lee13*

  • * Corresponding author: Kyung-Tae Lee ktlee@khu.ac.kr

  • † Equal contributors

Author Affiliations

1 Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University, Seoul 130-701, South Korea

2 Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung-Hee University, Seoul 130-701, South Korea

3 Department of Biomedical Science, College of Medical Science, Kyung-Hee University, Seoul 130-701, South Korea

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BMC Cancer 2009, 9:449  doi:10.1186/1471-2407-9-449

Published: 18 December 2009

Abstract

Background

Compound K [20-O-β-(D-glucopyranosyl)-20(S)-protopanaxadiol], a metabolite of the protopanaxadiol-type saponins of Panax ginseng C.A. Meyer, has been reported to possess anti-tumor properties to inhibit angiogenesis and to induce tumor apoptosis. In the present study, we investigated the effect of Compound K on apoptosis and explored the underlying mechanisms involved in HL-60 human leukemia cells.

Methods

We examined the effect of Compound K on the viabilities of various cancer cell lines using MTT assays. DAPI assay, Annexin V and PI double staining, Western blot assay and immunoprecipitation were used to determine the effect of Compound K on the induction of apoptosis.

Results

Compound K was found to inhibit the viability of HL-60 cells in a dose- and time-dependent manner with an IC50 of 14 μM. Moreover, this cell death had typical features of apoptosis, that is, DNA fragmentation, DNA ladder formation, and the externalization of Annexin V targeted phosphatidylserine residues in HL-60 cells. In addition, compound-K induced a series of intracellular events associated with both the mitochondrial- and death receptor-dependent apoptotic pathways, namely, (1) the activation of caspases-3, -8, and -9; (2) the loss of mitochondrial membrane potential; (3) the release of cytochrome c and Smac/DIABLO to the cytosol; (4) the translocation of Bid and Bax to mitochondria; and (5) the downregulations of Bcl-2 and Bcl-xL. Furthermore, a caspase-8 inhibitor completely abolished caspase-3 activation, Bid cleavage, and subsequent DNA fragmentation by Compound K. Interestingly, the activation of caspase-3 and -8 and DNA fragmentation were significantly prevented in the presence of cycloheximide, suggesting that Compound K-induced apoptosis is dependent on de novo protein synthesis.

Conclusions

The results indicate that caspase-8 plays a key role in Compound K-stimulated apoptosis via the activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation.