Panax ginseng has been reported to have cancer-preventive properties and, through anti-inflammatory, antioxidant, and pro-apoptotic mechanisms, to influence gene expression. However, the comparison of Korean white ginseng (WG) and red ginseng (RG) in their apoptotic effects and the identification of the selective cellular uptake of the ginsenosides in human breast cancer cells have not yet been fully understood. In the present study, the relative nonpolar and protopanaxadiol (PPD) class ginsenosides exhibited more cytotoxic and efficient cellular uptake on MCF-7 cells compared with the relative polar and protopanaxatriol (PPT) class compounds. PPD class ginsenosides were present in RG in a 2.5 times higher concentration as compared to WG, while PPT class ginsenosides were only present in WG. Thus, RG exerted more potent cytotoxicity than WG against MCF-7 and MDA-MB231 cells. RG also increased the sub-G1 DNA contents of the cell cycle and Annexin V-positive apoptotic bodies undergoing apoptosis through the caspase-3 activation in MCF-7 cells. In addition, RG downregulated the proliferative and anti-apoptotic gene products and potentiated paclitaxel-induced apoptosis in MCF-7 cells. Overall, RG contained a higher concentration of PPD class ginsenosides as compared to WG; the greater cellular uptake of PPD resulted in more substantial antiproliferative activity in human breast cancer cells.
Key words
Panax ginseng
- Araliaceae - LC‐MS - red ginseng - cancer - caspase‐3
References
1
Yun T K.
Panax ginseng – a non-organ-specific cancer preventive?.
Lancet Oncol.
2001;
2
49-55
2
Xiaoguang C, Hongyan L, Xiaohong L, Zhaodi F, Yan L, Lihua T, Rui H.
Cancer chemopreventive and therapeutic activities of red ginseng.
J Ethnopharmacol.
1998;
60
71-78
3
Keum Y S, Park K K, Lee J M, Chun K S, Park J H, Lee S K, Kwon H, Surh Y J.
Antioxidant and anti-tumor promoting activities of the methanol extract of heat-processed ginseng.
Cancer Lett.
2000;
150
41-48
4
Li W, Wanibuchi H, Salim E I, Wei M, Yamamoto S, Nishino H, Fukushima S.
Inhibition by ginseng of 1,2-dimethylhydrazine induction of aberrant crypt foci in the rat colon.
Nutr Cancer.
2000;
36
66-73
5
Park S E, Park C, Kim S H, Hossain M A, Kim M Y, Chung H Y, Son W S, Kim G Y, Choi Y H, Kim N D.
Korean red ginseng extract induces apoptosis and decreases telomerase activity in human leukemia cells.
J Ethnopharmacol.
2009;
121
304-312
6
Nurieva R I, Dedkova E N, Leont'eva G A, Abdrasilov B S, Pak Kh D, Kim Iu A, Zinchenko V P.
Mechanism of activation of Ehrlich ascites carcinoma cells using the total fraction of saponins from Korean ginseng.
Antibiot Khimioter.
1995;
40
25-28
7
Shin H J, Kim Y S, Kwak Y S, Song Y B, Park J D.
Enhancement of antitumor effects of paclitaxel (taxol) in combination with red ginseng acidic polysaccharide (RGAP).
Planta Med.
2004;
70
1033-1038
8
Choi C H, Kang G, Min Y D.
Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng.
Planta Med.
2003;
69
235-240
9
Kim S I, Park J H, Ryu J H, Park J D, Lee Y H, Kim T H, Kim J M, Baek N I.
Ginsenoside Rg5, a genuine dammarane glycoside from Korean red ginseng.
Arch Pharm Res.
1996;
19
551-553
11
Park I H, Kim N Y, Han S B, Kim J M, Kwon S W, Kim H J, Park M K, Park J H.
Three new dammarane glycosides from heat processed ginseng.
Arch Pharm Res.
2002;
25
428-432
12
Kim do Y, Park M W, Yuan H D, Lee H J, Kim S H, Chung S H.
Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells.
J Agric Food Chem.
2009;
57
10573-10578
13
Choi S, Kim T W, Singh S V.
Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by p 15 Ink4B and p 27 Kip1-dependent inhibition of cyclin-dependent kinases.
Pharm Res.
2009;
26
2280-2288
14
Kim S M, Lee S Y, Yuk D Y, Moon D C, Choi S S, Kim Y, Han S B, Oh K W, Hong J T.
Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel.
Arch Pharm Res.
2009;
32
755-765
16
Gaspar J R, Qu J, Straubinger N L, Straubinger R M.
Highly selective and sensitive assay for paclitaxel accumulation by tumor cells based on selective solid phase extraction and micro-flow liquid chromatography coupled to mass spectrometry.
Analyst.
2008;
133
1742-1748
17
Liu A, Pajkovic N, Pang Y, Zhu D, Calamini B, Mesecar A L, van Breemen R B.
Absorption and subcellular localization of lycopene in human prostate cancer cells.
Mol Cancer Ther.
2006;
5
2879-2885
18
Tian Q, Failla M L, Bohn T, Schwartz S J.
High-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry determination of cholesterol uptake by Caco-2 cells.
Rapid Commun Mass Spectrom.
2006;
20
3056-3060
19
Ha Y W, Ahn K S, Lee J C, Kim S H, Chung B C, Choi M H.
Validated quantification for selective cellular uptake of ginsenosides on MCF-7 human breast cancer cells by liquid chromatography-mass spectrometry.
Anal Bioanal Chem.
2010;
396
3017-3025
20
Ahn K S, Sethi G, Aggarwal B B.
Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products.
Mol Pharmacol.
2007;
71
209-219
21
Ahn K S, Sethi G, Sung B, Goel A, Ralhan R, Aggarwal B B.
Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1.
Cancer Res.
2008;
68
4406-4415
22
Ahn K S, Sethi G, Krishnan K, Aggarwal B B.
Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis.
J Biol Chem.
2007;
282
809-820
23
Koo J S, Choi W C, Rhee Y H, Lee H J, Lee E O, Ahn K S, Bae H S, Kang J M, Choi S U, Kim M O, Lu J, Kim S H.
Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells.
Life Sci.
2008;
83
700-708
24
Chou T C, Talalay P.
Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.
Adv Enzyme Regul.
1984;
22
27-55
25
Wang X, Zhao T, Gao X, Dan M, Zhou M, Jia W.
Simultaneous determination of 17 ginsenosides in rat urine by ultra performance liquid chromatography-mass spectrometry with solid-phase extraction.
Anal Chim Acta.
2007;
594
265-273
26
Yue P Y, Mak N K, Cheng Y K, Leung K W, Ng T B, Fan D T, Yeung H W, Wong R N.
Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides.
Chin Med.
2007;
2
6
27
Wang W, Zhao Y, Rayburn E R, Hill D L, Wang H, Zhang R.
In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng.
Cancer Chemother Pharmacol.
2007;
59
589-601
28
Yim H W, Jong H S, Kim T Y, Choi H H, Kim S G, Song S H, Kim J, Ko S G, Lee J W, Bang Y J.
Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis.
Cancer Res.
2005;
65
1952-1960
29
Fishbein A B, Wang C Z, Li X L, Mehendale S R, Sun S, Aung H H, Yuan C S.
Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng.
Arch Pharm Res.
2009;
32
505-513
30
Matsushime H, Roussel M F, Ashmun R A, Sherr C J.
Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
Cell.
1991;
65
701-713
32
Capalbo G, Rodel C, Stauber R H, Knauer S K, Bache M, Kappler M, Rodel F.
The role of survivin for radiation therapy. Prognostic and predictive factor and therapeutic target.
Strahlenther Onkol.
2007;
183
593-599
35
Choi H S, Kim K H, Sohn E, Park J D, Kim B O, Moon E Y, Rhee D K, Pyo S.
Red ginseng acidic polysaccharide (RGAP) in combination with IFN-gamma results in enhanced macrophage function through activation of the NF-kappaB pathway.
Biosci Biotechnol Biochem.
2008;
72
1817-1825
