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AIM 20 (s)-protopanaxadiol (PPD) is the metabolites of Ginseng saponin, including in both American ginseng (Panax quinquefolius L., Araliaceae) and Asian ginseng (Panax ginseng C.A.Meyer).In our previous study, we demonstrated that ginsenoside Rg3 (the glucoside of PPD) exhibited antiproliferative effects on HCT-116 cells and reduced the tumor size of nude mice implanted with the HCT116 ceils.Our subsequence study exposed that the anti-tumor proliferation effect of PPD was stronger than ginsenoside Rg3 in vitro, but little reporter was focus on the in vivo anticancer effect of PPD.This investigation is attempted to get more proofs about the effects of PPD to human colorectal cancer in vivo and in vitro, as well as to expose the mechanisms of action resulted by PPD in human colorectal cancer.METHODS The cytotoxicity of PPD was determined using MTI and crystal violet test.Cell cycle analysis was detected by flow cytometry (FCM) after propidium iodide (PI) fluorescence staining.The effects of PPD on colon cancer growth in vivo were determined using Xenograft Tumor Modal combined with Xenogen Bioluminescence Imaging.A novel cell-based assay was used for monitoring the influence of PPD to multiple cancer related-cells signaling pathways.The expression and activity of A kinase (PRKA) anchor protein 8 (AKAPA8L) and phosphatidylinositol transfer protein, alpha (PITPNA) (target genes from pervious microarray data) were analyzed by PCR and RNA interference studies.RESULTS PPD inhibited growth and induced cell cycle arrest in HCT116 ceils.Furthermore, PPD also inhibited tumor growth in athymic nude mice boating HCT116 cells as xenograft.Treating with PPD (30 mg·kg-1) for 1-3 weeks could reduce the tumor size of nude mice implanted with the HCT116 cells.PPD also changed the expression of AKAPAL8 and PITPNA.Reporter assay indicated PPD significantly suppressed the signals of NFκB, JNK and MAPK/ERK signaling pathways.CONCLUSION These results suggest that AKAPAL8 and PITPNA maybe, in part,related with NF-κB, JNK or MAPK/ERK signaling pathways.The anticancer activity of PPD in colon cancer cells is due to downregulation of NF-κB, JNK and MAPK/ERK signaling pathways and however, the mechanism of this response is cell context-dependent.