Abstract
BackgroundSome 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.MethodsEight 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.ResultsPPD 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.ConclusionsThis 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.
Highlights
Some of ginsenosides, root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts
We have demonstrated that cytotoxic effects of PPD on cancer cells were mediated through production of intracellular ceramides from membrane sphingomyelins
In our efforts to identify PPD-specific cytotoxic mechanisms in lipid rafts, we demonstrated that accumulated intracellular ceramides mediate cytotoxic effects of PPD, leading to growth inhibition and apoptosis in distinct cancer cells
Summary
Root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts. Due to its high concentrations in lipid rafts, long and saturated sphingolipids make microdomains physicochemically distinct from the remaining of plasma membranes abundant in short and unsaturated phospholipids through their closer interactions with cholesterols [4]. Cholesterol depleting agents such as methylβ-cyclodextrin (MβCD) can remove cholesterols out of lipid rafts, changing their physical properties and thereby modifying lipid raft-dependent signaling pathways in vital cellular processes [6]. Ginsenosides, phytosterols from Panax ginseng, are natural cholesterol derivatives with hydroxyl groups and oligosaccharide moieties, so many investigators have studied effects on which these ginsenosides might have against crucial functions of lipid rafts
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