Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 5, pp 589–601 | Cite as

In vitro anti-cancer activity and structure–activity relationships of natural products isolated from fruits of Panax ginseng

  • Wei Wang
  • Yuqing Zhao
  • Elizabeth R. Rayburn
  • Donald L. Hill
  • Hui Wang
  • Ruiwen ZhangEmail author
Original Article

Abstract

Purpose

Panax ginseng and its extracts have long been used for medical purposes; there is increasing interest in developing ginseng products as cancer preventive or therapeutic agents. The present study was designed to determine biological structure–activity relationships (SAR) for saponins present in Panax ginseng fruits.

Methods

Eleven saponins were extracted from P. ginseng fruits and purified by use of D101 resin and ordinary and reverse-phase silica gel column chromatography. Their chemical structures were elucidated on the basis of physicochemical constants and NMR spectra. Compounds were then evaluated for SAR with their in vitro cytotoxicity against several human cancer cell lines.

Results

The 11 compounds were identified as 20(R)-dammarane-3β,12β,20,25-tetrol (25-OH-PPD, 1); 20(R)-dammarane-3β,6α,12β,20,25-pentol (25-OH-PPT, 2); 20(S)-protopanaxadiol (PPD, 3); daucosterine 4, 20(S)-ginsenoside-Rh2 (Rh2, 5); 20(S)-ginsenoside-Rg3 (Rg3, 6); 20(S)-ginsenoside-Rg2 (Rg2, 7); 20(S)-ginsenoside-Rg1 (Rg1, 8); 20(S)-ginsenoside-Rd (Rd, 9); 20(S)-ginsenoside-Re (Re, 10); and 20(S)-ginsenoside-Rb1 (Rb1, 11). Among the eleven compounds, 1, 3 and 5 were the most effective inhibitors of cell growth and proliferation and inducers of apoptosis and cell cycle arrest. For 1, the IC50 values for most cell lines were in the range of 10–60 μM, at least twofold lower than for any of the other compounds. Compounds 1 and 3 had significant, dose-dependent effects on apoptosis, proliferation, and cell cycle progression.

Conclusions

The results suggest that the type of dammarane, the number of sugar moieties, and differences in the substituent groups affect their anti-cancer activity. This information may be useful for evaluating the structure/function relationship of other ginsenosides and their aglycones and for development of novel anticancer agents.

Keywords

Panax ginseng Chemical structure Anticancer Structure–activity relationship 

Notes

Acknowledgments

We thank Dr. Haiyan Chen for excellent technical assistance, and Drs. Robert Diasio, Sam Lee, and Xianglin Shi for helpful discussion. Y. Zhao was supported by a Liaoning Modernization TCM grant (LN403004), People's Republic of China, and in part by LN Xinzhong Modern Medicine Co., Ltd. H. Wang was supported in part by the funds from the UAB Cancer Pharmacology Laboratory.

References

  1. 1.
    Akao T, Kanaoka M, Kobashi K (1998) Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration – measurement of compound K by enzyme immunoassay. Biol Pharm Bull 21:245–249PubMedGoogle Scholar
  2. 2.
    Attele AS, Wu JA, Yuan CS (1999) Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 58:1685–1693PubMedCrossRefGoogle Scholar
  3. 3.
    Attele AS, Zhou YP, Xie JT, Wu JA, Zhang L, Dey L, Pugh W, Rue PA, Polonsky KS, Yuan CS (2002) Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 51:1851–1858PubMedGoogle Scholar
  4. 4.
    Bae EA, Han MJ, Kim EJ, Kim DH (2004) Transformation of ginseng saponins to ginsenoside Rh2 by acids and human intestinal bacteria and biological activities of their transformants. Arch Pharmacal Res 27:61–67CrossRefGoogle Scholar
  5. 5.
    Bae EA, Park SY, Kim DH (2000) Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull 23:1481–1485PubMedGoogle Scholar
  6. 6.
    Bespalov VG, Alexandrov VA, Limarenko AY, Voytenkov BO, Okulov VB, Kabulov MK, Peresunko AP, Slepyan LI, Davydov VV (2001) Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium. J Korean Med Sci 16:S42–S53PubMedGoogle Scholar
  7. 7.
    Chang YS, Seo EK, Gyllenhaal C, Block KI (2003) Panax ginseng: a role in cancer therapy? Integr Cancer Ther 2:13–33PubMedCrossRefGoogle Scholar
  8. 8.
    Chen YJ, Wang HY, Xu SX et al (1995) Study on the chemical constituents of Panax ginseng and their structure–function relationship anti-arrythmia and anti-tumor. Science Foundation China 9:46–48Google Scholar
  9. 9.
    Cheng YJ, Su SX, Ma QF, Pei YP, Xie H, Yao XS (1987) Studies on new minor saponins isolated from leaves of Panax ginseng CA Meyer. Yao Xue Xue Bao 22:685–689PubMedGoogle Scholar
  10. 10.
    Dharmananda SI (2002) The nature of ginseng: traditional use, modern research and the question of dosage. Herbal Gram 54:343–351Google Scholar
  11. 11.
    Hasegawa H, Uchiyama M (1998) Antimetastatic efficacy of orally administered ginsenoside Rb1 in dependence on intestinal bacterial hydrolyzing potential and significance of treatment with an active bacterial metabolite. Planta Med 64:696–700PubMedCrossRefGoogle Scholar
  12. 12.
    Helms S (2004) Cancer prevention and therapeutics: Panax ginseng. Alternative Med Rev 9:259–274Google Scholar
  13. 13.
    Kennedy DO, Scholey AB (2003) Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav 75:687–700PubMedCrossRefGoogle Scholar
  14. 14.
    Keum YS, Han SS, Chun KS, Park KK, Park JH, Lee SK, Surh YJ (2003) Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-kappaB activation and tumor promotion. Mutat Res 523–524:75–85PubMedGoogle Scholar
  15. 15.
    Keum YS, Park KK, Lee JM, Chun KS, Park JH, Lee SK, Surh YJ (2000) Antioxidant and anti-tumor promoting activities of the methanol extract of heat-processed ginseng. Cancer Lett 150:41–48PubMedCrossRefGoogle Scholar
  16. 16.
    Kim JY, Germolec DR, Luster MI (1990) Panax ginseng as a potential immunomodulator: studies in mice. Immonopharmacol Immunotoxicol 12:257–276Google Scholar
  17. 17.
    Kim TH, Lee YS, Cho CK, Park S, Choi SY, Yool SY (1996) Protective effect of ginseng on radiation-induced DNA double strand breaks and repair in murine lymphocytes. Cancer Biother Radiopharmaceut 11:267–272CrossRefGoogle Scholar
  18. 18.
    Kitts DD, Hu C (2000) Efficacy and safety of ginseng. Pub Health Nut 4:473–485Google Scholar
  19. 19.
    Kitts DD, Wijewickreme AN, Hu C (2000) Antioxidant properties of North American ginseng extract. Mol Cell Biochem 203:1–10PubMedCrossRefGoogle Scholar
  20. 20.
    Lee BH, Lee SJ, Hur JH, Lee S, Sung JH, Huh JD, Moon CK (1998) In vitro antigenotoxic activity of novel ginseng saponin metabolites formed by intestinal bacteria. Planta Med 64:500–503PubMedCrossRefGoogle Scholar
  21. 21.
    Lee SJ, Ko WG, Kim JH, Sung JH, Moon CK, Lee BH (2000) Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol 60:677–685PubMedCrossRefGoogle Scholar
  22. 22.
    Li M, Zhang Z, Hill D, Chen X, Wang H, Zhang R (2005) Genistein, a dietary isoflavone, down-regulates the MDM2 oncogene at both transcriptional and posttranslational levels. Cancer Res 65:8200–8208PubMedCrossRefGoogle Scholar
  23. 23.
    Li T S C (1995) Asian and American ginseng: a review. Hort Technology 5:27–34Google Scholar
  24. 24.
    Liu LW, Ye GC (2004) Clinical observation on inhibition of angiogenesis of thyroid cancer by Rg3. Chin J Cancer Prev Treat 11:957–958Google Scholar
  25. 25.
    Nakata H, Kikuchi Y, Tode T, Hirata J, Kita T, Ishii K, Kudoh K, Nagata I, Shinomiya N (1998) Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells. Jap J Cancer Res 98:733–740Google Scholar
  26. 26.
    Odashima S, Ohta T, Kohno H, Matsuda T, Kitagawa I, Abe H, Arishi S (1985) Control of phenotypic expression of cultured B16 melaonma cells by plant glycosides. Cancer Res 45:2781–2784PubMedGoogle Scholar
  27. 27.
    Oh GS, Pae HO, Choi BM, Seo EA, Kim DH, Shin MK, Kim JD, Kim JB Chung HT (2004) 20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factor-kappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide. Cancer Lett 205:23–29PubMedCrossRefGoogle Scholar
  28. 28.
    Ota T, Fujikawa-Yamamoto K, Zong ZP, Yamazaki M, Odashima S, Kitagawa I, Abe H, Arichi S (1987) Plant-glycoside modulation of cell surface related to control of differentiation in cultured B16 melanoma cells. Cancer Res 47:3863–3867PubMedGoogle Scholar
  29. 29.
    Park JA, Lee KY, Oh YJ, Kim KW, Lee SK (1997) Activation of caspase-3 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis. Cancer Lett 121:73–81PubMedCrossRefGoogle Scholar
  30. 30.
    Popovich DG, Kitts DD (2002) Structure–function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia (THP-1) cell line. Arch Biochem Biophys 406:1–8PubMedCrossRefGoogle Scholar
  31. 31.
    Rhee YH, Ahn JH, Choe J, Kang KW, Joe C (1991) Inhibition of mutagenesis and transformation by root extracts of Panax ginseng in vitro. Planta Med 57:125–128PubMedCrossRefGoogle Scholar
  32. 32.
    Sato K, Mochizuki M, Saiki I, Yoo YC, Samukawa K, Azuma I (1994) Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2. Biol Pharmaceut Bull 17:635–639Google Scholar
  33. 33.
    Shibata S (2001) Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Korean Med Sci 16:S28–S37PubMedGoogle Scholar
  34. 34.
    Suh SO, Kroh M, Kim NR, Joh YG, Cho MY (2002) Effects of red ginseng upon postoperative immunity and survival in patients with state III gastric cancer. Am J Chinese Med 30:483–494CrossRefGoogle Scholar
  35. 35.
    Wakabayashi C, Hasegawa H, Murata J, Saiki I (1997) In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. Oncol Res 9:411–417PubMedGoogle Scholar
  36. 36.
    Wang H, Cai Q, Zeng X, Yu D, Agrawal S, Zhang R (1999) Anti-tumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to RIα subunit of protein kinase A after oral administration. Proc Natl Acad Sci USA 96:13989–13994PubMedCrossRefGoogle Scholar
  37. 37.
    Wang H, Yu D, Agrawal S, Zhang R (2003) Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixed-backbone antisense oligonucleotides: In vitro and in vivo activities and mechanisms. Prostate 54:194–205PubMedCrossRefGoogle Scholar
  38. 38.
    Wei TX, Chang LY, Wang JF, Edmund F, Morika J, Heinrich P, Chen WS, Eberhard B (1982) Zwei neue Dammarane-sapogenine aus den Blättern von Panax notoginseng. Plant Med 1982 45:167–171Google Scholar
  39. 39.
    Wu XG, Zhu DH, Li X (2001) Anticarcinogenic effect of red ginseng on the development of liver cancer induced by diethylnitrosamine in rats. J Korean Med Sci 16:S61–S65PubMedGoogle Scholar
  40. 40.
    Xie JT, Wang CZ, Wang AB, Wu J, Basila D, Yuan CS (2005) Antihyperglycemic effects of total ginsenosides from leaves and stem of Panax ginseng. Acta Pharmacol Sin 26:1104–1110PubMedCrossRefGoogle Scholar
  41. 41.
    Yun TK, Choi SY (1995) Preventive effect of ginseng intake against various human cancers: a case-control study on 1987 pairs. Cancer Epidemiol Biomarkers Prev 4:401–408PubMedGoogle Scholar
  42. 42.
    Yun TK, Yun YS, Han IW (1983) Anticarcinogenic effect of long-term oral administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detection Prev 6:515–525Google Scholar
  43. 43.
    Zhang Z, Li M, Wang H, Agrawal S, Zhang R (2003) Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci USA 100:11636–11641PubMedCrossRefGoogle Scholar
  44. 44.
    Zhao YQ, Yuan CL, Fu YQ, Wei XJ, Zhu HJ, Chen YJ, Wu LJ, Li X (1990) Chemical studies of minor triterpene compounds isolated from the stems and leaves of Panax ginseng CA Meyer. Yao Xue Xue Bao 25:297–301PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Wei Wang
    • 1
  • Yuqing Zhao
    • 1
    • 3
  • Elizabeth R. Rayburn
    • 1
  • Donald L. Hill
    • 1
    • 2
  • Hui Wang
    • 1
    • 2
    • 4
  • Ruiwen Zhang
    • 1
    • 2
    • 4
    Email author
  1. 1.Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Cancer Pharmacology LaboratoryUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Shenyang Pharmaceutical UniversityShenyangPeople’s Republic of China
  4. 4.Institute for Nutritional Sciences, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiPeople’s Republic of China

Personalised recommendations