Ginseng saponin metabolite induces apoptosis in MCF-7 breast cancer cells through the modulation of AMP-activated protein kinase

Kim, Areum Daseul; Kang, Kyoung Ah; Zhang, Rui; Lim, Chang Hwy; Kim, Hee Sun; Kim, Dong Hyun; Jeon, You Jin; Lee, Young Moo; Park, Jinny; Chang, Weon Young; Hyun, Jin Won

doi:10.1016/j.etap.2010.04.008

Cited by 50 publications

(48 citation statements)

References 46 publications

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“…C-K was the major metabolite formed during the hydrolysis of red ginseng extract by mouse fecal homogenate. C-K has been shown to be active against multiple cancer cells ( Chae et al, 2009;Kim et al, 2010;Wang et al, 2012), including against LM1 cells (Supplemental Fig. 2).…”

Section: Hydrolysis Of Ginsenoside By Glycosidases Derived From Gutmentioning

confidence: 99%

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Yang

Wang²,

Niu³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Ginsenosides are hydrolyzed extensively by gut microflora after oral administration, and their metabolites are pharmacologically active against lung cancer cells. In this study, we measured the metabolism of various ginsenosides by gut microflora and determined the mechanisms responsible for the observed pharmacokinetic behaviors of its active metabolite, Compound K (C-K). The results showed that biotransformation into C-K is the major metabolic pathway of ginsenosides after the oral administration of the red ginseng extract containing both protopanaxadiol and protopanaxatriol ginsenosides. Pharmacokinetic studies in normal mice showed that C-K exhibited low oral bioavailability. To define the mechanisms responsible for this low bioavailability, two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, were used, and their presence substantially decreased C-K's efflux ratio in Caco-2 cells (from 26.6 to <3) and significantly increased intracellular concentrations (by as much as 40-fold). Similar results were obtained when transcellular transport of C-K was determined using multidrug resistance 1 (MDR1)-overexpressing Madin-Darby canine kidney II cells. In MDR1a/b(؊/؊) FVB mice, its plasma C max and AUC 0-24h were increased substantially by 4.0-and 11.7-fold, respectively. These increases appear to be due to slower elimination and faster absorption of C-K in MDR1a/b(؊/؊) mice. In conclusion, C-K is the major active metabolite of ginsenosides after microflora hydrolysis of primary ginsenosides in the red ginseng extract, and inhibition/deficiency of P-gp can lead to large enhancement of its absorption and bioavailability.

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Section: Hydrolysis Of Ginsenoside By Glycosidases Derived From Gutmentioning

confidence: 99%

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Yang

Wang²,

Niu³

et al. 2012

Drug Metab Dispos

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“…However, among Bulgarian herbs TT is the one that is known to contain a big fraction of saponins, mainly protodioscin [4]. A lot of studies have been performed on plant extracts and have reported that saponins exert an antitumor effect on various cancer types [5][6][7]. Saponins from TT have been found to suppress proliferation and induce apoptosis in fibroblast cells [8] and to activate apoptotic processes in breast cancer cells [9].…”

Section: Tribulus Terrestris Lmentioning

confidence: 99%

Changes in gene expression of CXCR4, CCR7 and BCL2 after treatment of breast cancer cells with saponin extract from Tribulus terrestris

Goranova¹,

Ss²,

Vs³

et al. 2015

neo

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Saponins are natural substances produced by a large number of plants, one of which is Tribulus terrestris L. (TT). They have been reported to possess an antitumor activity exerted by regulating various signaling pathways in the cell. Although the mechanisms of action of saponin extracts from various plants have been widely studied, limited data are available about TT. The present study aimed to analyze the impact of saponin extract from TT on cell processes in breast carcinoma cell lines. The variations in expression of a group of 32 selected genes were examined by real-time PCR after saponin treatment of MCF7 and MCF10A cell lines. Only three genes -CXCR4, CCR7 and BCL2, showed changes in their mRNA levels after the application of the herb extract. While CXCR4 expression was reduced in both cell lines, CCR7 and BCL2 levels decreased only in tumorigenic MCF7 cells, implying cell-specificity of the saponin action. Our results suggested that TT extract containing saponins was likely to affect the processes of apoptosis and metastasizing of cancer cells. Further in vivo studies will show its applicability as an anticancer therapeutic agent.

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“…Apoptosis analysis was performed using an Annexin V-FITC Apoptosis Detection Kit II (BD Bioscience, San Jose, CA, USA) according to the manufacturer's instructions. Briefly, cells were plated at 2x10 5 cells/ well in 6-well plates, incubated overnight, and treated with the indicated concentrations of widdrol for 24 h. Cells were harvested, washed with PBS, and combined with a binding buffer containing Annexin-V-FITC and propidium iodide. Following a 15-min incubation in the dark, cells were analyzed by flow cytometry using a FACSCalibur flow cytometer (BD Bioscience).…”

Section: Widdrol Induces Apoptosis Via Activation Of Amp-activated Prmentioning

confidence: 99%

“…Recently, AMPK has also been identified as a potential target for cancer prevention and/or treatment (3). Indeed, a variety of AMPK activators have been shown to exert anticancer effects (4)(5)(6). Especially, metformin, an orally available biguanide derivative that is widely used for the treatment of Type 2 diabetes, was shown to exert anticancer effects by activation of AMPK and is currently being investigated in clinical trials (4).…”

Section: Introductionmentioning

confidence: 99%

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells

Kang

Park²,

Lee³

et al. 2012

Oncol Rep

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Abstract. Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose-and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase-3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation. IntroductionAMP-activated protein kinase (AMPK), a serine/threonine protein kinase conserved in eukaryotes, is known as a cellular energy sensor involved in the regulation of the response to environmental or nutritional stress (1). AMPK is a heterotrimeric complex composed of catalytic α subunit and regulatory β and γ subunits. AMPK is activated in response to energy deprivation and the activation of AMPK regulates a variety of cellular processes, such as hepatic fatty acid oxidation, lipogenesis, glycogen synthesis and glucose uptake (2). Recently, AMPK has also been identified as a potential target for cancer prevention and/or treatment (3). Indeed, a variety of AMPK activators have been shown to exert anticancer effects (4-6). Especially, metformin, an orally available biguanide derivative that is widely used for the treatment of Type 2 diabetes, was shown to exert anticancer effects by activation of AMPK and is currently being investigated in clinical trials (4). AMPK is also reported to be linked with tumor suppressors, such as liver kinase B1 (LBK1), p21, p53 and tuberous sclerosis complex 2 (TSC2), indicating that AMPK is a potential therapeutic target for cancer (7-9).The leaves of Juniperus chinensis have been reported to contain a lignan with strong anti-leukemic and antitumor activities (10) and a sesquiterpene with anti-fungal activity (11). Widdrol is an odorant derivative contained in various plants of Juniperus sp., including J. chinensis and J. lucayana (12,13). In a previous study, widdrol was shown to induce cell cycle arrest in HT-29 cells (13). To find additional mechanisms involved in the anticancer activity of widdrol, we examined whether widdrol induces apoptosis and characterized molecular mecha...

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Ginseng saponin metabolite induces apoptosis in MCF-7 breast cancer cells through the modulation of AMP-activated protein kinase

Cited by 50 publications

References 46 publications

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Changes in gene expression of CXCR4, CCR7 and BCL2 after treatment of breast cancer cells with saponin extract from Tribulus terrestris

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells

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