Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Fermented Ginseng Extract, BST204, Inhibits Proliferation and Motility of Human Colon Cancer Cells

  • Received : 2010.11.25
  • Accepted : 2011.01.14
  • Published : 2011.04.30
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Abstract

Panax ginseng CA Meyer, a herb from the Araliaceae, has traditionally been used as a medicinal plant in Asian countries. Ginseng extract fermented by ginsenoside-${\beta}$-glucosidase treatment is enriched in ginsenosides such as Rh2 and Rg3. Here we show that a fermented ginseng extract, BST204, has anti-proliferative and anti-invasive effects on HT-29 human colon cancer cells. Treatment of HT-29 cells with BST204 induced cell cycle arrest at $G_1$ phase without progression to apoptosis. This cell cycle arrest was accompanied by up-regulation of tumor suppressor proteins, p53 and p21$^{WAF1/Cip1}$, down-regulation of the cyclin-dependent kinase/cyclins, Cdk2, cyclin E, and cyclin D1 involved in $G_1$ or $G_1/S$ transition, and decrease in the phosphorylated form of retinoblastoma protein. In addition, BST204 suppressed the migration of HT-29 cells induced by 12-O-tetradecanoylphorbol-13-acetate, which correlated with the inhibition of metalloproteinase-9 activity and extracellular signal-regulated kinase activity. The effects of BST204 on the proliferation and the invasiveness of HT-29 cells were similar to those of Rh2. Taken together, the results suggest that fermentation of ginseng extract with ginsenoside-${\beta}$-glucosidase enhanced the anti-proliferative and the anti-invasive activity against human colon cancer cells and these anti-tumor effects of BST204 might be mediated in part by enriched Rh2.

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References

  1. Arnott, C. H., Scott, K. A., Moore, R. J., Hewer, A., Phillips, D. H., Parker, P., Balkwill, F. R. and Owens, D. M. (2002) Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway. Oncogene. 21, 4728-4738. https://doi.org/10.1038/sj.onc.1205588
  2. Attele, A. S., Wu, J. A. and Yuan, C. S. (1999) Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol. 58, 1685-1693. https://doi.org/10.1016/S0006-2952(99)00212-9
  3. Bocca, C., Bozzo, F., Cannito, S., Colombatto, S. and Miglietta, A. (2009) CLA reduces breast cancer cell growth and invasion through ERalpha and PI3K/Akt pathways. Chem. Biol. Interact. 186, 250-251.
  4. Bourguignon, L. Y., Gunja-Smith, Z., Iida, N., Zhu, H. B., Young, L. J., Muller, W. J. and Cardiff, R. D. (1998) CD44v(3,8-10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells. J. Cell. Physiol. 176, 206-215. https://doi.org/10.1002/(SICI)1097-4652(199807)176:1<206::AID-JCP22>3.0.CO;2-3
  5. Cheng, C. C., Yang, S. M., Huang, C. Y., Chen, J. C., Chang, W. M. and Hsu, S. L. (2005) Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother Pharmacol. 55, 531-540. https://doi.org/10.1007/s00280-004-0919-6
  6. Cho, H. J., Kang, J. H., Kwak, J. Y., Lee, T. S., Lee, I. S., Park, N. G., Nakajima, H., Magae, J. and Chang, Y. C. (2007). Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms. Carcinogenesis. 28, 1104-1110.
  7. Choi, S., Kim, T. W. and Singh, S. V. (2009) Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by p15 Ink4B and p27 Kip1-dependent Inhibition of cyclindependent kinases. Pharm. Res. 26, 2280-2288. https://doi.org/10.1007/s11095-009-9944-9
  8. Chou Chou, C. C. and Hsu, C. Y. (2009) Involvement of PKC in TPApotentiated apoptosis induction during hemin-mediated erythroid differentiation in K562 cells. Naunyn. Schmiedebergs Arch. Pharmacol. 379, 1-9.
  9. el-Deiry, W. S, Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W. and Vogelstein, B. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell. 75, 817-825 https://doi.org/10.1016/0092-8674(93)90500-P
  10. Eun, D. W., Ahn, S. H., You, J. S., Park, J. W., Lee, E. K., Lee, H. N., Kang, G. M., Lee, J. C., Choi, W. S., Seo, D. W. and Han, J. W. (2007) PKCepsilon is essential for gelsolin expression by histone deacetylase inhibitor apicidin in human cervix cancer cells. Biochem. Biophys. Res. Commun. 354, 769-775. https://doi.org/10.1016/j.bbrc.2007.01.046
  11. Fei, X. F., Wang, B. X., Tashiro, S., Li, T. J., Ma, J. S. and Ikejima, T. (2002) Apoptotic effects of ginsenoside Rh2 on human malignant melanoma A375-S2 cells. Acta. Pharmacol. Sin. 23, 315-322.
  12. Gartel, A. L. and Tyner, A. L. (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp. Cell Res. 246, 280-289. https://doi.org/10.1006/excr.1998.4319
  13. Grutter, M. G. (2000) Caspases: key players in programmed cell death. Curr. Opin. Struct. Biol. 10, 649-655. https://doi.org/10.1016/S0959-440X(00)00146-9
  14. Han, J. W., Ahn, S. H., Park, S. H., Wang, S. Y., Bae, G. U., Seo, D. W., Kwon, H. K., Hong, S., Lee, H. Y., Lee, Y. W. and Lee, H. W. (2000) Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. Cancer Res. 60, 6068-6074
  15. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. and Elledge, S. J. (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 75, 805-816. https://doi.org/10.1016/0092-8674(93)90499-G
  16. Jackson, J. G. and Pereira-Smith, O. M. (2006) Primary and compensatory roles for RB family members at cell cycle gene promoters that are deacetylated and downregulated in doxorubicin-induced senescence of breast cancer cells. Mol. Cell Biol. 26, 2501-2510. https://doi.org/10.1128/MCB.26.7.2501-2510.2006
  17. Jin, Y. H., Yoo, K. J., Lee, Y. H. and Lee, S. K. (2000) Caspase 3-mediated cleavage of p21WAF1/CIP1 associated with the cyclin Acyclin-dependent kinase 2 complex is a prerequisite for apoptosis in SK-HEP-1 cells. J. Biol. Chem. 275, 30256-30263. https://doi.org/10.1074/jbc.M001902200
  18. Johnson, G. L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912. https://doi.org/10.1126/science.1072682
  19. Kim, S., Kang, J. K., Kim, Y. K., Seo, D. W., Ahn, S. H., Lee, J. C., Lee, C. H., You, J. S., Cho, E. J., Lee, H. W. and Han, J. W. (2006a) Histone deacetylase inhibitor apicidin induces cyclin E expression through Sp1 sites. Biochem. Biophys. Res. Commun. 342, 1168-1173. https://doi.org/10.1016/j.bbrc.2006.02.081
  20. Kim, S. Y., Kim, D. H., Han, S. J., Hyun, J. W. and Kim, H. S. (2007) Repression of matrix metalloproteinase gene expression by ginsenoside Rh2 in human astroglioma cells. Biochem. Pharmacol. 74, 1642-1651. https://doi.org/10.1016/j.bcp.2007.08.015
  21. Kim, W. Y., Kim, J. M., Han, S. B., Lee, S. K., Kim, N. D., Park, M. K., Kim, C. K. and Park, J. H. (2000) Steaming of ginseng at high temperature enhances biological activity. J. Nat. Prod. 63, 1702-1704. https://doi.org/10.1021/np990152b
  22. Kim, Y. K., Lee, E. K., Kang, J. K., Kim, J. A., You, J. S., Park, J. H., Seo, D. W., Hwang, J. W., Kim, S. N., Lee, H. Y., Lee, H. W. and Han, J. W. (2006b) Activation of NF-kappaB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: its implication for resistance to apoptosis. Cell Death Differ. 13, 2033-2041. https://doi.org/10.1038/sj.cdd.4401915
  23. Kitts, D. D., Wijewickreme, A. N. and Hu, C. (2000) Antioxidant properties of a North American ginseng extract. Mol. Cell Biochem. 203, 1-10. https://doi.org/10.1023/A:1007078414639
  24. Kumar, A., Kumar, M., Park, T. Y., Park, M. H., Takemoto, T., Terado, T., Kitano, M. and Kimura, H. (2009) Molecular mechanisms of ginsenoside Rp1-mediated growth arrest and apoptosis. Int. J. Mol. Med. 24, 381-386
  25. Kwon, S. H., Ahn, S. H., Kim, Y. K., Bae, G. U., Yoon, J. W., Hong, S., Lee, H. Y., Lee, Y. W., Lee, H. W. and Han, J. W. (2002) Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J. Biol. Chem. 277, 2073-2080. https://doi.org/10.1074/jbc.M106699200
  26. Lee, K. Y., Park, J. A., Chung, E., Lee, Y. H., Kim, S. I. and Lee, S. K. (1996) Ginsenoside-Rh2 blocks the cell cycle of SK-HEP-1 cells at the G1/S boundary by selectively inducing the protein expression of p27kip1. Cancer Lett. 110, 193-200. https://doi.org/10.1016/S0304-3835(96)04502-8
  27. Liu, T. G, Huang, Y., Cui, D. D., Huang, X. B., Mao, S. H., Ji, L. L., Song, H. B. and Yi, C. (2009) Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer. 9, 250. https://doi.org/10.1186/1471-2407-9-250
  28. Maekawa, R., Maki, H., Yoshida, H., Hojo, K., Tanaka, H., Wada, T., Uchida, N., Takeda, Y., Kasai, H., Okamoto, H., Tsuzuki, H., Kambayashi, Y., Watanabe, F., Kawada, K., Toda, K., Ohtani, M., Sugita, K. and Yoshioka, T. (1999) Correlation of antiangiogenic and antitumor effi cacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor. Cancer Res. 59, 1231-1235.
  29. Mehendale, S. R., Wang, C. Z., Shao, Z. H., Li, C. Q., Xie, J. T., Aung, H. H. and Yuan, C. S. (2006) Chronic pretreatment with American ginseng berry and its polyphenolic constituents attenuate oxidant stress in cardiomyocytes. Eur. J. Pharmacol. 553, 209-214 https://doi.org/10.1016/j.ejphar.2006.09.051
  30. Mittnacht, S. (1998) Control of pRB phosphorylation. Curr. Opin. Genet. Dev. 8, 21-27. https://doi.org/10.1016/S0959-437X(98)80057-9
  31. Nakata, H., Kikuchi, Y., Tode, T., Hirata, J., Kita, T., Ishii, K., Kudoh, K., Nagata, I. and Shinomiya, N. (1998) Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells. Jpn. J. Cancer Res. 89, 733-740. https://doi.org/10.1111/j.1349-7006.1998.tb03278.x
  32. Nishimoto, S. and Nishida, E. (2006) MAPK signalling: ERK5 versus ERK1/2. EMBO Rep. 7, 782-786. https://doi.org/10.1038/sj.embor.7400755
  33. Oh, J. I., Chun, K. H., Joo, S. H., Oh, Y. T. and Lee, S. K. (2005) Caspase-3-dependent protein kinase C delta activity is required for the progression of Ginsenoside-Rh2-induced apoptosis in SK-HEP-1 cells. Cancer Lett. 230, 228-238. https://doi.org/10.1016/j.canlet.2004.12.043
  34. Park, J. A., Lee, K. Y., Oh, Y. J., Kim, K. W. and Lee, S. K. (1997) Activation of caspase-3 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis. Cancer Lett. 121, 73-81. https://doi.org/10.1016/S0304-3835(97)00333-9
  35. Popovich, D. G. and Kitts, D. D. (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, 1-8. https://doi.org/10.1016/S0003-9861(02)00398-3
  36. Rosenblum, G., Meroueh, S. O., Kleifeld, O., Brown, S., Singson, S. P., Fridman, R., Mobashery, S. and Sagi, I. (2003) Structural basis for potent slow binding inhibition of human matrix metalloproteinase-2 (MMP-2). J. Biol. Chem. 278, 27009-27015. https://doi.org/10.1074/jbc.M301139200
  37. Saya, H. Molecular mechanism regulating effect of anti-cancer agents. (2009) Gan To Kagaku Ryoho. 36, 1-5.
  38. Seo, J. Y., Lee, J. H., Kim, N. W., Her, E., Chang, S. H., Ko, N. Y., Yoo, Y. H., Kim, J. W., Seo, D. W., Han, J. W., Kim, Y. M. and Choi, W. S. (2005a). Effect of a fermented ginseng extract, BST204, on the expression of cyclooxygenase-2 in murine macrophages. Int. Immunopharmacol. 5, 929-936. https://doi.org/10.1016/j.intimp.2005.01.008
  39. Seo, J. Y., Lee, J. H., Kim, N. W., Kim, Y. J., Chang, S. H., Ko, N. Y., Her, E., Yoo, Y. H., Kim, J. W., Lee, B. Y., Lee, H. Y., Kim, Y. M. and Choi, W. S. (2005b) Inhibitory effects of a fermented ginseng extract, BST204, on the expression of inducible nitric oxide synthase and nitric oxide production in lipopolysaccharide-activated murine macrophages. J. Pharm. Pharmacol. 57, 911-918. https://doi.org/10.1211/0022357056497
  40. Shamamian, P., Schwartz, J. D., Pocock, B. J., Monea, S., Whiting, D., Marcus, S. G. and Mignatti, P. (2001) Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for infl ammatory cells in tumor invasion and angiogenesis. J. Cell Physiol. 189, 197-206. https://doi.org/10.1002/jcp.10014
  41. Tachikawa, E., Kudo, K., Harada, K., Kashimoto, T., Miyate, Y., Kakizaki, A. and Takahashi, E. (1999) Effects of ginseng saponins on responses induced by various receptor stimuli. Eur. J. Pharmacol. 369, 23-32. https://doi.org/10.1016/S0014-2999(99)00043-6
  42. Tanno, S., Tanno, S., Mitsuuchi, Y., Altomare, D. A., Xiao, G. H. and Testa, J. R. (2001) AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res. 61, 589-593.
  43. Ura, H., Bonfi l, R. D., Reich, R., Reddel, R., Pfeifer, A., Harris, C. C. and Klein-Szanto, A. J. (1989) Expression of type IV collagenase and procollagen genes and its correlation with the tumorigenic, invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells. Cancer Res. 49, 4615-4621.
  44. Wang, C. Z., Zhang, B., Song, W. X., Wang, A., Ni, M., Luo, X., Aung, H. H., Xie, J. T., Tong, R., He, T. C. and Yuan, C. S. (2006) Steamed American ginseng berry: ginsenoside analyses and anticancer activities. J. Agric. Food Chem. 54, 9936-9942. https://doi.org/10.1021/jf062467k
  45. Wu, Q., Liu, S., Ding, L., Ye, X. and Su, W. (2002) PKCalpha translocation from mitochondria to nucleus is closely related to induction of apoptosis in gastric cancer cells. Sci. China. C. Life. Sci. 45, 237-244. https://doi.org/10.1360/02yc9026
  46. Yun, T. K. (2003) Experimental and epidemiological evidence on nonorgan specifi c cancer preventive effect of Korean ginseng and identifi cation of active compounds. Mutat. Res. 523, 63-74.

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