Planta Med 2011; 77(2): 133-140
DOI: 10.1055/s-0030-1250160
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Cellular Uptake of Ginsenosides in Korean White Ginseng and Red Ginseng and Their Apoptotic Activities in Human Breast Cancer Cells

Jung Il Lee1 [*] , Young Wan Ha4 [*] , Tae Won Choi1 , Hyun Jung Kim1 , Sung-Moo Kim1 , Hyeung-Jin Jang2 , Jung-Hye Choi3 , Man Ho Choi4 , Bong Chul Chung4 , Gautam Sethi5 , Sung-Hoon Kim1 , Kyoo Seok Ahn1 , Seung-Hoon Choi1 , Bum Sang Shim1 , Kwang Seok Ahn1
  • 1Department of Oriental Pathology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
  • 2Department of Biochemistry, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
  • 3Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
  • 4Life/Health Division, Korea Institute of Science and Technology, Seoul, Republic of Korea
  • 5Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Further Information

Publication History

received February 1, 2010 revised June 23, 2010

accepted June 25, 2010

Publication Date:
28 July 2010 (online)

Abstract

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.

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
  • 10 Ryu J H, Park J H, Eun J H, Jung J H, Sohn D H. A dammarane glycoside from Korean red ginseng.  Phytochemistry. 1997;  44 931-933
  • 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
  • 15 Bi X, Zhao Y, Fang W, Yang W. Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: targetting beta-catenin signalling.  Clin Exp Pharmacol Physiol. 2009;  36 1074-1078
  • 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
  • 31 Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy.  Expert Opin Ther Targets. 2008;  12 463-476
  • 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
  • 33 Nicholson D W, Thornberry N A. Caspases: killer proteases.  Trends Biochem Sci. 1997;  22 299-306
  • 34 Rowinsky E K, Cazenave L A, Donehower R C. Taxol: a novel investigational antimicrotubule agent.  J Natl Cancer Inst. 1990;  82 1247-1259
  • 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

1 These authors contributed equally to this study.

Dr. Kwang Seok Ahn

Department of Oriental Pathology
College of Oriental Medicine
Kyung Hee University

1 Hoegi-Dong Dongdaemun-Gu

130-701 Seoul

Republic of Korea

Phone: + 82 29 61 23 16

Fax: + 82 29 61 23 16

Email: ksahn@khu.ac.kr