title: Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways.
abstract: Plant-derived active constituents and their semi-synthetic or synthetic analogs have served as major sources of anticancer drugs. 20(S)-protopanaxadiol (PPD) is a metabolite of ginseng saponin of both American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A. Meyer). We previously demonstrated that ginsenoside Rg3, a glucoside precursor of PPD, exhibits anti-proliferative effects on HCT116 cells and reduces tumor size in a xenograft model. Our subsequent study indicated that PPD has more potent antitumor activity than that of Rg3 in vitro although the mechanism underlying the anticancer activity of PPD remains to be defined. Here, we investigated the mechanism underlying the anticancer activity of PPD in human cancer cells in vitro and in vivo. PPD was shown to inhibit growth and induce cell cycle arrest in HCT116 cells. The in vivo studies indicate that PPD inhibits xenograft tumor growth in athymic nude mice bearing HCT116 cells. The xenograft tumor size was significantly reduced when the animals were treated with PPD (30 mg/kg body weight) for 3 weeks. When the expression of previously identified Rg3 targets, A kinase (PRKA) anchor protein 8 (AKAP8L) and phosphatidylinositol transfer protein α (PITPNA), was analyzed, PPD was shown to inhibit the expression of PITPNA while upregulating AKAP8L expression in HCT116 cells. Pathway-specific reporter assays indicated that PPD effectively suppressed the NF-κB, JNK and MAPK/ERK signaling pathways. Taken together, our results suggest that the anticancer activity of PPD in colon cancer cells may be mediated through targeting NF-κB, JNK and MAPK/ERK signaling pathways, although the detailed mechanisms underlying the anticancer mode of PPD action need to be fully elucidated.
authors: Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China. jianligao@gmail.com
authors: Jian-Li
authors: JL
authors: Gao
authors: Gui-Yuan
authors: GY
authors: Lv
authors: Bai-Cheng
authors: BC
authors: He
authors: Bing-Qiang
authors: BQ
authors: Zhang
authors: Hongyu
authors: H
authors: Zhang
authors: Ning
authors: N
authors: Wang
authors: Chong-Zhi
authors: CZ
authors: Wang
authors: Wei
authors: W
authors: Du
authors: Chun-Su
authors: CS
authors: Yuan
authors: Tong-Chuan
authors: TC
authors: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000096:biosynthesis; D005894:Panax; D049294:Phospholipid Transfer Proteins / Q000096:biosynthesis; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D012502:Sapogenins / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C490117:AKAP8L protein, human; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C493463:PITPNA protein, human; D049294:Phospholipid Transfer Proteins; D010936:Plant Extracts; D012502:Sapogenins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C062916:protopanaxadiol
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