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Open Access Research article

Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells

Bonggoo Park16, Yong-Moon Lee3, Jae-Sung Kim4, Youl Her5, Ju Hee Kang2, Seung-Hyun Oh1 and Hwan-Mook Kim1*

Author Affiliations

1 College of Pharmacy, Gachon University, Incheon, Korea

2 National Cancer Center, Gyeonggi-do, Goyang-si, Republic of Korea

3 Department of Manufacturing Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju, Korea

4 Division of Biology of Aging, Department of Surgery, University of Florida, Gainesville, FL, USA

5 BTGin Co. Ltd., Daejeon, Korea

6 Current address: Department of Biochem and Mol Biol, College of Medicine, Korea University, GRL, Seoul, Korea

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BMC Complementary and Alternative Medicine 2013, 13:194  doi:10.1186/1472-6882-13-194

Published: 27 July 2013

Abstract

Background

Some of ginsenosides, root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts. Protopanaxadiol (PPD) exhibits the highest cytotoxic effect among 8 ginsenosides which we evaluated for anti-cancer activity. We investigated if PPD disrupts lipid rafts in its cytotoxic effects and also the possible mechanisms.

Methods

Eight ginsenosides were evaluated using different cancer cells and cell viability assays. The potent ginsenoside, PPD was investigated for its roles in lipid raft disruption and downstream pathways to apoptosis of cancer cells. Anti-cancer effects of PPD was also investigated in vivo using mouse xenograft model.

Results

PPD consistently exerts its potent cytotoxicity in 2 cell survival assays using 5 different cancer cell lines. PPD disrupts lipid rafts in different ways from methyl-β-cyclodextrin (MβCD) depleting cholesterol out of the subdomains, since lipid raft proteins were differentially modulated by the saponin. During disruption of lipid rafts, PPD activated neutral sphingomyelinase 2 (nSMase 2) hydrolyzing membrane sphingomyelins into pro-apoptotic intracellular ceramides. Furthermore, PPD demonstrated its anti-cancer activities against K562 tumor cells in mouse xenograft model, confirming its potential as an adjunct or chemotherapeutic agent by itself in vivo.

Conclusions

This study demonstrates that neutral sphingomyelinase 2 is responsible for the cytotoxicity of PPD through production of apoptotic ceramides from membrane sphingomyelins. Thus neutral sphingomyelinase 2 and its relevant mechanisms may potentially be employed in cancer chemotherapies.

Keywords:
Protopanaxadiol; Lipid raft; Neutral sphingomyelinase; Ceramide; Chemosensitization