Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-induced Cell Death of Human Astrocytoma Cells Through Distinct Apoptotic Signaling Pathways

Abstract

I n t r o d u c t i o nGlioblastoma multiforme (GBM) is the most malignant and common brain tumor and it comprises ~23% of all primary brain tumors in adults. These malignancies are refractory to all the current therapeutic approaches, including surgery, radiotherapy and chemotherapy. Fas (CD95 or APO-1) is a member of the TNF/NGF receptor family, and Fas induces caspase-dependent apoptotic death in various transformed cells (1,2). Fas ligation with natural ligand or agonistic anti-Fas antibody is followed by recruitment of proapoptotic adaptor molecules such as Fas-associated death domain (FADD) to transduce the apoptotic signals through the caspase cascades (3). In some cells, Fas efficiently activates caspase-8 and it subsequently activates caspase-3 or 7, while other types of Fasinduced apoptosis are mediated by cytochrome-C release from the mitochondria and this is inhibited by the over-expression of antiapoptotic bcl-2 family members (4).Panax Ginseng is known for its biological and pharmacological activities such as its anti-cancer, anti-aging, anti-inflammatory and anti-oxidant properties in the nervous, immune and circulatory systems (5). These diverse physiological activities of ginseng are mainly mediated by saponin, which is a ginsenoside. Especially, the metabolites of ginsenosides that are formed by enteric bacteria have been focused on for their pharmacological activities. Among them, compound K (C-K) is known to be formed by enteric bacterial fermentation of Rb1, Rb2 and RC, and C-K has been reported to suppress tumor metastasis and inflammatory responses (6,7). Another ginsenoside Rh2, a metabolite of Rg3, is also known for its tumor suppression by inducing apoptosis or retarding growth signals (8).We have previously shown that human malignant astrocytoma cells are quite resistant to Fas-induced apoptosis even though these Cancer Res Treat. 2009;41(1):36-44 Purpose Malignant astrocytomas are among the commonest primary brain tumors and they have a grave prognosis, and so there is an urgent need to develop effective treatment. In this study, we investigated the molecular mechanisms that are responsible for the anti-tumor effect of ginsenosides on human astrocytoma cells. Materials and MethodsWe tested 13 different ginsenosides for their anti-tumor effect on human malignant astrocytoma cells in conjunction with Fas stimulation. In addition, the cell signaling pathways were explored by using pharmacological inhibitors and performing immunoblot analysis. DCF-DA staining and antioxidant experiments were performed to investigate the role of reactive oxygen species as one of the apoptosis-inducing mechanisms. ResultsAmong the 13 different ginsenoside metabolites, compound K and Rh2 induced apoptotic cell death of the astrocytoma cells in a caspase-and p38 MAPK-dependent manner, yet the same treatment had no cytotoxic effect on the primary cultured human astrocytes. Combined treatment with ginsenosides and Fas ligand showed a synergistic cytotoxic effect, which was mediated by the reduction of intracell...

Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis

“…*Pp0.01 compared with TRAIL-alone treated samples act as anti-apoptotic mediators. 13,37 We further confirmed that PKCd is also involved in FasL-mediated signaling (Supplementary Figure 7). Reactive oxygen species, particularly H 2 O 2 , have been recognized as second messengers in receptor-mediated signaling processes including proliferation, inflammation, and apoptosis.…”

Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor

“…CK is rapidly absorbed in the gastrointestinal tract and is retained for a long time in rat plasma [20,21]. The anti-angiogenic effect of CK was also reported [14,16,22]. Although the anti-cancer effects of ginsenosides have been studied extensively in other cancer models, the effect of ginsenosides on NPC is unknown.…”

Identification and Characterization of the Rhizobium sp. Strain GIN611 Glycoside Oxidoreductase Resulting in the Deglycosylation of Ginsenosides

“…Therefore, the deglycosylated forms often show better pharmacological activity in the body than the glycosylated forms (17,21). For example, the ginsenosides compound K (CK) and Rh2, which are widely known as inducers of tumor cell apoptosis (10,18), are deglycosylated into PPD. Compared to Rh2, PPD shows better pharmacological effects on B16 melanoma cells (28).…”