Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin

Lee, Sang-Jun; Sung, Jong-Hwan; Lee, Sang-Joo; Moon, Chang-Kiu; Lee, Byung‐Hoon

doi:10.1016/s0304-3835(99)00188-3

Cited by 133 publications

(92 citation statements)

References 14 publications

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“…Scale ¼ 50 mm. Although M1 was also reported to have an anticancer effect (Wakabayashi et al, 1998;Lee et al, 1999), no target molecule of M1 has been clarified. Knowing the target and signal transduction of M1 may elucidate the mechanism of axonal formation.…”

Section: Discussionmentioning

confidence: 99%

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Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

Tohda

Hashimoto

Kuboyama

et al. 2005

Neuropsychopharmacol

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We previously showed that 20-O-b-D-glucopyranosyl-20(S)-protopanaxadiol (M1), a metabolite of protopanaxadiol-type ginseng saponins by intestinal bacteria had axonal extension activity in degenerated neurons, and improved memory disorder and synaptic loss induced by an active fragment of amyloid b, Ab(25-35). It is unknown how M1 shows these effects in neurons. To clarify the signal transduction mechanism of M1-induced axonal extension, phosphorylated proteins by M1 stimulation were identified because most cellular signal pathways are regulated by phosphorylation/dephosphorylation. The combination of immunoprecipitation and MALDI-TOF-MS revealed that teneurin-2 and mPar3 were specifically phosphorylated by M1 stimulation. Because mPar3 is known as an axonal specifying molecule and to be regulated by phosphatidylinositol 3-kinase (PI3-kinase), the involvement of teneurin-2 and PI3-kinase in the M1 signal was studied. In teneurin-2-deficient cortical neurons, M1-induced axonal extension and PI3-kinase activation were significantly inhibited. In addition, treatment with PI3-kinase inhibitor also reduced M1-induced axonal extension. These results suggest that M1 induces axonal outgrowth through the teneurin-2FPI3-kinase cascade.

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Section: Discussionmentioning

confidence: 99%

“…M1 was also reported to have anticancer effect (Wakabayashi et al, 1998;Lee et al, 1999) in addition to axonal regeneration and antidementia effects. Binding molecules and the signal transduction mechanism of M1, however, is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

Tohda

Hashimoto

Kuboyama

et al. 2005

Neuropsychopharmacol

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“…A similar finding was reported in the literature. The ginseng saponin Rb1 metabolic pathway was Rb 1 ÑRdÑF 2 ÑCompound K by human intestinal bacteria, and F 2 and Compound K only differ in one glucose moiety, but Compound K has stronger anti-tumor activities both in vivo and in vitro [20,21]. In addition, the animal studies indicate that ADS-I has significant inhibitory effects, on Lewis lung cancer and liver cancer in nude mice (SMMC-7721) after oral administration [3][4][5][6][7], but in our previous study, ADS-I was barely absorbed through the gastrointestinal tract after oral administration in rats [8].…”

Section: Discussionmentioning

confidence: 99%

Ardipusilloside-I Metabolites from Human Intestinal Bacteria and Their Antitumor Activity

Cao

Wang

et al. 2015

Molecules

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Ardipusilloside-I (ADS-I) is a triterpenoid saponin extracted from Ardisia pusilla DC, and has been demonstrated to have potent antitumor activity. However, ADS-I metabolism in humans has not been investigated. In this study, we studied the biotransformation of ADS-I in human intestinal bacteria, and examined the in vitro antitumor activity of the major metabolites. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to detect ADS-I biotransformation products, and their chemical structures were identified by high performance liquid chromatography-nuclear magnetic resonance (HPLC-NMR). The antitumor activity of the major metabolites was determined by the MTT assay. Here, we show that main reaction seen in the metabolism of ADS-I in human intestinal bacteria was deglycosylation, which produced a total of four metabolites. The structures of the two major metabolites M1 and M2 were confirmed by using NMR. MTT assay showed that ADS-I metabolites M1 and M2 have the same levels of inhibitory activities as ADS-I in cultured SMMC-7721 cells and MCF-7 cells. In conclusion, this study demonstrates deglycosylation as a primary pathway of ADS-I metabolism in human intestinal bacteria, and suggests that the pharmacological activity of ADS-I may be mediated, at least in part, by its metabolites.

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“…The ability of higher concentrations of alc-GE to inhibit cell proliferation cannot be explained by ER modulation, as ginseng/ginsenosides inhibit the proliferation of a number of cancer cell lines, most of which do not express estrogen receptors. [32][33][34][35] The estrogenic effects of low concentrations of alc-GE may be mediated by those ginsenosides known to elicit estrogenic responses, such as Rb1, Rh1, or Rg1, [21][22][23][24]36 or other unknown steroidal compounds that are of necessary abundance to elicit a response. The estrogenic ginsenoside Rb1 is one of the most abundant ginsenosides found in methanol-extracted P quinquefolium root.…”

Section: Discussionmentioning

confidence: 99%

Extraction-Dependent Effects of American Ginseng (Panax quinquefolium) on Human Breast Cancer Cell Proliferation and Estrogen Receptor Activation

2006

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Hypothesis:Ginseng root extracts and the biologically active ginsenosides have been shown to inhibit proliferation of human cancer cell lines, including breast cancer. However, there are conflicting data that suggest that ginseng extracts (GEs) may or may not have estrogenic action, which might be contraindicated in individuals with estrogen-dependent cancers. The current study was designed to address the hypothesis that the extraction method of American ginseng (Panax quinquefolium) root will dictate its ability to produce an estrogenic response using the estrogen receptor (ER)-positive MCF-7 human breast cancer cell model. Methods: MCF-7 cells were treated with a wide concentration range of either methanol-(alc-GE) or water-extracted (w-GE) ginseng root for 6 days. Cells were grown in media containing either normal or charcoal-stripped fetal calf serum to limit exposure to exogenous estrogen. Thus, an increase in MCF-7 cell proliferation by GE indicated potential estrogenicity. This was confirmed by blocking GE-induced MCF-7 cell proliferation with ER antagonists ICI 182,780 (1 nM) and 4-hydroxytamoxifen (0.1 µ µM). Furthermore, the ability of GE to bind ERα α or ERβ β and stimulate estrogen-responsive genes was examined. Results: Alc-GE, but not w-GE, was able to increase MCF-7 cell proliferation at low concentrations (5-100 µ µg/mL) when cells were maintained under low-estrogen conditions. The stimulatory effect of alc-GE on MCF-7 cell proliferation was blocked by the ER antagonists ICI 182,780 or 4-hydroxytamoxifen. At higher concentrations of GE, both extracts inhibited MCF-7 and ER-negative MDA-MB-231 cell proliferation regardless of media conditions. Binding assays demonstrated that alc-GE, but not w-GE, was able to bind ERα α and ERβ β. Alc-GE (50 µ µg/mL) also induced an approximate 2.5-fold increase in expression of the estrogenresponsive pS2 gene, as well as progesterone receptor (PgR) gene expression, whereas w-GE was without effect. Conclusion: These data indicate that low concentrations of alc-GE, but not w-GE, elicit estrogenic effects, as evidenced by increased MCF-7 cell proliferation, in a manner antagonized by ER antagonists, interactions of alc-GE with estrogen receptors, and increased expression of estrogenresponsive genes by alc-GE. Thus, discrepant results between different laboratories may be due to the type of GE being analyzed for estrogenic activity.

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Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin

Cited by 133 publications

References 14 publications

Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

Ardipusilloside-I Metabolites from Human Intestinal Bacteria and Their Antitumor Activity

Extraction-Dependent Effects of American Ginseng (Panax quinquefolium) on Human Breast Cancer Cell Proliferation and Estrogen Receptor Activation

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