Planta Med 2016; 82(08): 705-711
DOI: 10.1055/s-0042-101764
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Antitumoral Activity of (20R)- and (20S)-Ginsenoside Rh2 on Transplanted Hepatocellular Carcinoma in Mice

Qun Lv
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
,
Na Rong
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
,
Li-Jia Liu
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
,
Xiao-Lin Xu
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
,
Jian-Ting Liu
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
,
Feng-Xie Jin
2   School of Biological & Foodstuff Engineering, Dalian Institute of Light Industry, Dalian, China
,
Chun-Mei Wang
1   Department of Biological Pharmaceutics, School of Materia Medica, Beijing University of Chinese Medicine, Beijing, China
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 20. Juli 2015
revised 14. Dezember 2015

accepted 05. Januar 2016

Publikationsdatum:
10. Mai 2016 (online)

Abstract

Hepatocellular carcinoma is one of the leading causes of malignancy-related death in China. Its therapy in clinics is a big challenge. Ginsenoside Rh2 is one of the most notable cancer-preventing components from red ginseng and it has been reported that ginsenoside Rh2 exhibited potent cytotoxicity against human hepatoma cells. Rh2 exists as two different stereoisomeric forms, (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2. Previous reports showed that the Rh2 epimers demonstrated different pharmacological activities and only (20S)-ginsenoside Rh2 showed potent proliferation inhibition on cancer cells in vitro. However, the in vivo anti-hepatoma activity of (20R)-ginsenoside Rh2 and (20S)-ginsenoside Rh2 has not been reported yet. This work assessed and compared the anti-hepatoma activities of (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 using H22 a hepatoma-bearing mouse model in vivo. In addition, hematoxylin and eosin staining, the deoxynucleotidyl transferase dUTP nick-end labeling assay, and the semiquantitative reverse transcriptase polymerase chain reaction method were used to further study the apoptosis of the tumors. The results showed that both (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 suppressed the growth of H22 transplanted tumors in vivo, and the highest inhibition rate could be up to 42.2 and 46.8 %, respectively (p < 0.05). Further, hematoxylin/eosin staining and the deoxynucleotidyl transferase dUTP nick-end labeling assay indicated that both (20R)-ginsenoside Rh2 and (20S)-ginsenoside Rh2 could induce H22 hepatoma tumor cell apoptosis, with apoptosis indexes of 3.87 %, and 3.80 %, respectively (p < 0.05). Moreover, this effect was accompanied by downregulating the level of Bcl-2 mRNA. In conclusion, both (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 can suppress the growth of H22 hepatomas without causing severe side effects, and this effect is associated with the induction of apoptosis.

 
  • References

  • 1 Tan B, Huang JF, Wei Q, Zhang H, Ni RZ. Anti-hepatoma effect of arsenic trioxide on experimental liver cancer induced by 2-acetamidofluorene in rats. World J Gastroenterol 2005; 11: 5938-5943
  • 2 Zhu ZZ, Cong WM, Liu SF, Dong H, Zhu GS, Wu MC. Homozygosity for Pro of p 53 Arg72Pro as a potential risk factor for hepatocellular carcinoma in Chinese population. World J Gastroenterol 2005; 11: 289-292
  • 3 Yue PY, Mak NK, Cheng YK, Leung KW, Ng TB, Fan DT, Yeung HW, Wong RN. Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides. Chin Med 2007; 2: 6
  • 4 Hwang JT, Kim SH, Lee MS, Kim SH, Yang HJ, Kim MJ, Kim HS, Ha J, Kim MS, Kwon DY. Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3 T3-L1 adipocyte. Biochem Biophys Res Commun 2007; 364: 1002-1008
  • 5 Wang H, Yu P, Gou H, Zhang J, Zhu M, Wang Z, Tian J, Jiang Y, Fu F. Cardioprotective effects of 20(S)-ginsenoside Rh2 against doxorubicin-induced cardiotoxicity in vitro and in vivo . Evid Based Complement Alternat Med 2012; 2012: 506214
  • 6 Lian LH, Jin Q, Song SZ, Wu YL, Bai T, Jiang S, Li Q, Yang N, Nan JX. Ginsenoside Rh2 downregulates LPS-induced NF-κB activation through inhibition of TAK1 phosphorylation in RAW 264.7 murine macrophage. Evid Based Complement Alternat Med 2013; 2013: 646728
  • 7 He L, Lee J, Jang JH, Lee SH, Nan MH, Oh BC, Lee SG, Kim HH, Soung NK, Ahn JS, Kim BY. Ginsenoside Rh2 inhibits osteoclastogenesis through down-regulation of NF-κB, NFATc1 and c-Fos. Bone 2012; 50: 1207-1213
  • 8 Wang Z, Zheng Q, Liu K, Li G, Zheng R. Ginsenoside Rh(2) enhances antitumour activity and decreases genotoxic effect of cyclophosphamide. Basic Clin Pharmacol Toxicol 2006; 98: 411-415
  • 9 Dong H, Bai LP, Wong VK, Zhou H, Wang JR, Liu Y, Jiang ZH, Liu L. The in vitro structure-related anti-cancer activity of ginsenosides and their derivatives. Molecules 2011; 16: 10619-10630
  • 10 Yue PYK, Huang Y, Wong RNS. Ginsenoside Rg3 and Rh2: the anti-cancer and anti- angiogenic saponins from Ginseng. In: Atta-ur-Rahman, Iqbal Choudhary M, editors Anti-angiogenesis drug discovery and development, Vol. 1. Sharjah, U.A.E.: Bentham e-Book; 2011: 34-57
  • 11 Guo XX, Guo Q, Li Y, Lee SK, Wei XN, Jin YH. Ginsenoside Rh2 induces human hepatoma cell apoptosis via bax/bak triggered cytochrome C release and caspase-9/caspase-8 activation. Int J Mol Sci 2012; 13: 15523-15535
  • 12 Liu Y, Zhang X, Chen S, Zhao Y. Induce apoptosis effect of ginsenoside Rh2 on HepG2 cells. Zhongguo Shiyan Zhenduanxue 2011; 15: 2011-2013
  • 13 He X, He J, Zhang Y. 何鑫,何剪太,张阳德. 人参皂苷Rh2对人肝癌Bel-7402细胞增殖和凋亡的影响. 中国现代医学杂志 [Effects of ginsenoside Rh2 on the proliferation and apoptosis of human hepatocarcinoma cells Bel-7402]. China J Mod Med 2012; 22: 24-27
  • 14 Zeng XL, Tu ZG. Induction of differentiation by ginsenoside Rh2 in hepatocarcinoma cell SMMC-7721. Chin J Cancer 2004; 23: 879-884
  • 15 Cao M, Zhang J, Zhao Y, Song X, Ma B. Advances in Ginsenoside Rh2 and Its Derivatives. World Sci Tech 2012; 14: 2205-2211
  • 16 Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol 2007; 39: 1489-1499
  • 17 FDAʼs policy statement on the development of new stereoisomeric drugs. Chirality 1992; 4: 338-340
  • 18 Liu J, Shiono J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R. 20 (R)-ginsenoside Rh2, not 20 (S), is a selective osteoclastgenesis inhibitor without any cytotoxicity. Bioorg Med Chem Lett 2009; 19: 3320-3323
  • 19 Oh SJ, Lee S, Choi WY, Lim CJ. Skin anti-photoaging properties of ginsenoside Rh2 epimers in UV-B-irradiated human keratinocyte cells. J Biosci 2014; 39: 673-682
  • 20 Liu J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R. Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia 2010; 81: 902-905
  • 21 Tao L, Gao F, Fu Z, Han R. Inhibition effect of 20(R)-ginsenoside Rh2 skin tumor-bearing mice induced by DMBA/croton oil. Lishizhen Med Mater Med Res 2006; 17: 1950-1954
  • 22 Tao L, Liu H, Han R. 陶丽华, 刘红岩, 韩锐. 人参皂苷Rh2抗B16-BL6黑色素瘤转移的作用. 辽宁中医杂志 [Inhibitory effect of 20(R)-ginsenoside Rh2 on B16 melanom a metastasis]. Liaoning J Tradit Chin Med 2006; 33: 1505-1506
  • 23 Gu Y, Wang GJ, Wu XL, Zheng YT, Zhang JW, Ai H, Sun JG, Jia YW. Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters. Xenobiotica 2010; 40: 602-612
  • 24 Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003; 31: 1065-1071
  • 25 Zhang J, Zhou F, Niu F, Lu M, Wu X, Sun J, Wang G. Stereoselective regulations of P-glycoprotein by ginsenoside Rh2 epimers and the potential mechanisms from the view of pharmacokinetics. PLoS One 2012; 7: e35768
  • 26 Bae SH, Park JB, Zheng YF, Jiang MJ, Kim SO, Kim JY, Yoo YH, Yoon KD, Oh E, Bae SK. Pharmacokinetics and tissue distribution of ginsenoside Rh2 and Rg3 epimers after oral administration of BST204, a purified ginseng dry extract, in rats. Xenobiotica 2014; 44: 1099-1107
  • 27 Wu R, Ru Q, Chen L, Ma B, Li C. Stereospecificity of ginsenoside Rg3 in the promotion of cellular immunity in hepatoma H22-bearing mice. J Food Sci 2014; 79: H1430-H1435
  • 28 Qian T, Cai Z, Wong RN, Mak NK, Jiang ZH. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 816: 223-232
  • 29 Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc 2008; 2008: pdb.prot4986