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Multiple mechanisms of apoptosis induced by 20(S)-protopanaxadiol (aPPD) in glioma cells Liu, Guo Yu

Abstract

Ginsenosides are major pharmaceutical components in ginseng, cytotoxicity of ginsenoside Rh2, which exists in ginseng extract with trace concentrations, on cancer cells has been known. In our previous study, we identified that Careseng®, a specially formulated ginseng product, had the equal cytotoxicity on tumor cells as Rh2. In this study I investigated the mechanism of apoptosis in glioma cells with different PTEN and P53 status induced by 20(S) protopanaxadiol (aPPD), which is a derivative of Rh2 and the major constituent of Careseng®. aPPD can be obtained in lower cost from ginseng. Firstly, based on the viability analysis and DNA staining of U87MG (PTEN negative and wild type p53) and SF188 (PTEN positive and p53 mutant) cells treated by aPPD, it was found that aPPD, as effectively as Rh2, rapidly induced apoptosis in two glioma cell lines. The cell apoptosis of U87MG and SF188 cells induced by aPPD was confirmed by DNA fragmentation, TUNEL DNA-staining, typical apoptotic nuclear changes and cell membrane blebbing. By Western Blot analysis, it was demonstrated that caspase-3, -7, -8 and -9 were activated in the SF188 cells with dose- and time-response relationship to aPPD treatment but not in the U87MG cells, and found that cells with caspase activation revealed much more sensitive to aPPD treatment than those without caspase activation. Phosphorylated Akt on Ser473 was significantly decreased in U87MG but not SF188 cells. APPD-caused increase in intensity of superoxide anion and number of positive cells in both cell lines. Antioxidant gene activator, tBHQ or general caspase inhibitor partially blocked the aPPD-induced cell when applied alone but demonstrated a nearly complete protection when used together in SF188 cells. Although, INK phosphorylation was significantly increased in aPPD treated glioma cells, their activation was not related to the apoptosis as INK inhibitors had effect on the cell viability. The above results suggest that aPPD is a promising candidate for anti-cancer agent that induces apoptosis in a wide spectrum of cancer types. The bioactivity of aPPD is related to multiple signalling pathways and apoptosis induced by aPPD may be mediated by different mechanisms in different cells.

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