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Research article

References

  1. Vo HT, Cho JY, Choi YE, Choi YS, Jeong YH. 2015. Kinetic study for the optimization of ginsenoside Rg3 production by heat treatment of ginsenoside Rb1. J. Ginseng Res. 39: 304-313.
    Pubmed PMC CrossRef
  2. Quan LH, Kim YJ, Li GH, Choi KT, Yang DC. 2013. Microbial transformation of ginsenoside Rb1 to compound K by Lactobacillus paralimentarius. World J. Microbiol. Biotechnol. 29: 1001-1007.
    Pubmed CrossRef
  3. Park CS, Yoo MH, Noh KH, Oh DK. 2010. Biotransformation of ginsenosides by hydrolyzing the sugar moieties of ginsenosides using microbial glycosidases. Appl. Microbiol. Biotechmol. 87: 9-19.
    Pubmed CrossRef
  4. Cui L, Wu SQ, Zhao CA, Yin CR. 2016. Microbial conversion of major ginsenosides in ginseng total saponins by Platycodon grandiflorum endophytes. J. Ginseng Res. 40: 366-374.
    Pubmed PMC CrossRef
  5. Hong H, Cui CH, Kim JK, Jin FX, Kim SC, Im WT. 2012. Enzymatic biotransformation of ginsenoside Rb1 and gypenoside XVII into ginsenosides Rd and F2 by recombinant β-glucosidase from Flavobacterium johnsoniae. J. Ginseng Res. 36: 418-424.
    Pubmed PMC CrossRef
  6. Wang Y, Choi KD, Yu HS, Jin F, Im YT. 2016. Production of ginsenoside F1 using commercial enzyme Cellulase KN. J. Ginseng Res. 40: 121-126.
    Pubmed PMC CrossRef
  7. Choi HS, Kim SY, Park Y, Jung EY, Suh HJ. 2014. Enzymatic transformation of ginsenosides in Korean red ginseng (Panax ginseng Meyer) extract prepared by spezyme and optidex. J. Ginseng Res. 38: 264-269.
    Pubmed PMC CrossRef
  8. Chi H, Kim DH, Ji GE. 2005. Transformation of ginsenosides Rb2 and Rc from Panax ginseng by food microorganisms. Biol. Pharm. Bull. 28: 2102-2105.
    Pubmed CrossRef
  9. Quan K, Liu Q, Wan JY, Zhao YJ, Guo RZ, Alolga RN, et al. 2015. Rapid preparation of rare ginsenosides by acid transformation and their structure-activity relationships against cancer cells. Sci. Rep. 5: 8598.
    Pubmed PMC CrossRef
  10. Tang XP, Tang GD, Fang CY, Liang ZH, Zhang LY. 2013. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J. Gastroenterol. 19: 1582-1592.
    Pubmed PMC CrossRef
  11. Xia T, Wang JC, Xu W, Xu LH, Lao CH, Ye QX, et al. 2014. 20(S)-Ginsenoside Rh2 induces apoptosis in human leukaemia Reh cells through mitochondrial signaling pathways. Biol. Pharm. Bull. 37: 248-254.
    Pubmed CrossRef
  12. Guo XX, Li Y, Sun C, Jiang D, Lin YJ, Jin FX, et al. 2014. p53-dependent Fas expression is critical for ginsenoside Rh2 triggered caspase-8 activation in HeLa cells. Protein Cell 5: 224-234.
    Pubmed PMC CrossRef
  13. Shi Q, Li J, Feng Z, Zhao L, Luo L, You Z, et al. 2014. Effect of ginsenoside Rh2 on the migratory ability of HepG2 liver carcinoma cells: recruiting histone deacetylase and inhibiting activator protein 1 transcription factors. Mol. Med. Rep. 10: 1779-1785.
    CrossRef
  14. Yang Z, Zhao T, Liu H, Zhang L. 2016. Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy. Sci. Rep. 6: 19383.
    Pubmed PMC CrossRef
  15. Tung NH, Song GY, Minh CV, Kiem PV, Jin LG, Boo HJ, et al. 2010. Steamed ginseng-leaf components enhance cytotoxic effects on human leukemia HL-60 cells. Chem. Pharm Bull. 58: 1111-1115.
    CrossRef
  16. Vinoth Kumar R, Oh TW, Park YK. 2016. Anti-inflammatory effects of ginsenoside-Rh2 inhibits LPS-induced activation of microglia and overproduction of inflammatory mediators via modulation of TGF-beta1/Smad pathway. Neurochem. Res. 41: 951-957.
    Pubmed CrossRef
  17. Hwang JT, Kim SH, Lee MS, Kim SH, Yang HJ, Kim MJ, et al. 2007. Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. Biochem. Biophys. Res. Commun. 364: 1002-1008.
    Pubmed CrossRef
  18. Hou J, Xue J, Wang C, Liu L, Zhang D, Wang Z, et al. 2012. Microbial transformation of ginsenoside Rg3 to ginsenoside Rh2 by Esteya vermicola CNU 120806. World J. Microbiol. Biotechnol. 28: 1807-1811.
    Pubmed CrossRef
  19. 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. Pharm. Res. 27: 61-67.
    Pubmed CrossRef
  20. Kim JK, Cui CH, Liu Q, Yoon MH, Kim SC, Im WT. 2013. Mass production of the ginsenoside Rg3(S) through the combinative use of two glycoside hydrolases. Food Chem. 141: 1369-1377.
    Pubmed CrossRef
  21. Cui CH, Kim JK, Kim SC, Im WT. 2014. Characterization of a ginsenoside-transforming β-glucosidase from Paenibacillus mucilaginosus and its application for enhanced production of minor ginsenoside F2. PLoS One 9: e85727.
    Pubmed PMC CrossRef
  22. Du J, Cui CH, Park SC, Kim JK, Yu HS, Jin FX, et al. 2014. Identification and characterization of a ginsenoside-transforming β-glucosidase from Pseudonocardia sp. Gsoil 1536 and its application for enhanced production of minor ginsenoside Rg2(S). PLoS One 9: e96914.
    Pubmed PMC CrossRef
  23. Cui CH, Liu QM, Kim JK, Sung BH, Kim SG, Kim SC, et al. 2013. Identification and characterization of a Mucilaginibacter sp. strain QM49 β-glucosidase and its use in the production of the pharmaceutically active minor ginsenosides (S)-Rh1 and (S)-Rg2. Appl. Environ. Microbiol. 79: 5788-5798.
    Pubmed PMC CrossRef
  24. Liu J, Shiono J, Shimizu K, Yu H, Zhang C, Jin F, et al. 2009. 20(R)-Ginsenoside Rh2, not 20(S), is a selective osteoclastgenesis inhibitor without any cytotoxicity. Bioorg. Med. Chem. Lett. 19: 3320-3323.
    Pubmed CrossRef
  25. Liu J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R. 2010. Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia 81: 902-905.
    Pubmed CrossRef
  26. Shi J, Cao B, Zha WB, Wu XL, Liu LS, Xiao WJ, et al. 2013. Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo. Acta Pharmacol. Sin. 34: 1349-1358.
    Pubmed PMC CrossRef
  27. Quan LH, Jin Y, Wang C, Min JW, Kim YJ, Yang DC. 2012. Enzymatic transformation of the major ginsenoside Rb2 to minor compound Y and compound K by a ginsenosidehydrolyzing β-glycosidase from Microbacterium esteraromaticum. J. Ind. Microbiol. Biotechnol. 39: 1557-1562.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2017; 27(7): 1233-1241

Published online July 28, 2017 https://doi.org/10.4014/jmb.1701.01077

Copyright © The Korean Society for Microbiology and Biotechnology.

Production of the Rare Ginsenoside Rh2-MIX (20(S)-Rh2, 20(R)-Rh2, Rk2, and Rh3) by Enzymatic Conversion Combined with Acid Treatment and Evaluation of Its Anti-Cancer Activity

Bong-Kyu Song 1, 2, Kyeng Min Kim 1, 2, Kang-Duk Choi 1, 2 and Wan-Taek Im 1, 2*

1Department of Biotechnology, Hankyong National University, Anseong 17579, Republic of Korea, 2Genomic Informatics Center, Graduate School of Future Convergence Technology, Hankyong National University, Anseong 17579, Republic of Korea

Received: February 2, 2017; Accepted: May 2, 2017

Abstract

The ginsenoside Rh2 has strong anti-cancer, anti-inflammatory, and anti-diabetic effects.
However, the application of ginsenoside Rh2 is restricted because of the small amounts found
in Korean white and red ginsengs. To enhance the production of ginsenoside Rh2-MIX
(comprising 20(S)-Rh2, 20(R)-Rh2, Rk2, and Rh3 as a 10-g unit) with high specificity, yield, and
purity, a new combination of enzymatic conversion using the commercial enzyme Viscozyme
L followed by acid treatment was developed. Viscozyme L treatment at pH 5.0 and 50°C was
used initially to transform the major ginsenosides Rb1, Rb2, Rc, and Rd into ginsenoside F2,
followed by acid-heat treatment using citric acid 2% (w/v) at pH 2.0 and 121°C for 15 min.
Scale-up production in a 10-L jar fermenter, using 60 g of the protopanaxadiol-type
ginsenoside mixture from ginseng roots, produced 24 g of ginsenoside Rh2-MIX. Using 2 g of
Rh2-MIX, 131 mg of 20(S)-Rh2, 58 mg of 20(R)-Rh2, 47 mg of Rk2, and 26 mg of Rh3 were
obtained at over 98% chromatographic purity. Then, the anti-cancer effect of the four purified
ginsenosides was investigated on B16F10, MDA-MB-231, and HuH-7 cell lines. As a result,
these four rare ginsenosides markedly inhibited the growth of the cancer cell lines. These
results suggested that rare ginsenoside Rh2-MIX could be exploited to prepare an anti-cancer
supplement in the functional food and pharmaceutical industries.

Keywords: Biotransformation, ginsenoside, ginsenoside Rh2, Viscozyme L, mass production, acid-heat treatment

References

  1. Vo HT, Cho JY, Choi YE, Choi YS, Jeong YH. 2015. Kinetic study for the optimization of ginsenoside Rg3 production by heat treatment of ginsenoside Rb1. J. Ginseng Res. 39: 304-313.
    Pubmed KoreaMed CrossRef
  2. Quan LH, Kim YJ, Li GH, Choi KT, Yang DC. 2013. Microbial transformation of ginsenoside Rb1 to compound K by Lactobacillus paralimentarius. World J. Microbiol. Biotechnol. 29: 1001-1007.
    Pubmed CrossRef
  3. Park CS, Yoo MH, Noh KH, Oh DK. 2010. Biotransformation of ginsenosides by hydrolyzing the sugar moieties of ginsenosides using microbial glycosidases. Appl. Microbiol. Biotechmol. 87: 9-19.
    Pubmed CrossRef
  4. Cui L, Wu SQ, Zhao CA, Yin CR. 2016. Microbial conversion of major ginsenosides in ginseng total saponins by Platycodon grandiflorum endophytes. J. Ginseng Res. 40: 366-374.
    Pubmed KoreaMed CrossRef
  5. Hong H, Cui CH, Kim JK, Jin FX, Kim SC, Im WT. 2012. Enzymatic biotransformation of ginsenoside Rb1 and gypenoside XVII into ginsenosides Rd and F2 by recombinant β-glucosidase from Flavobacterium johnsoniae. J. Ginseng Res. 36: 418-424.
    Pubmed KoreaMed CrossRef
  6. Wang Y, Choi KD, Yu HS, Jin F, Im YT. 2016. Production of ginsenoside F1 using commercial enzyme Cellulase KN. J. Ginseng Res. 40: 121-126.
    Pubmed KoreaMed CrossRef
  7. Choi HS, Kim SY, Park Y, Jung EY, Suh HJ. 2014. Enzymatic transformation of ginsenosides in Korean red ginseng (Panax ginseng Meyer) extract prepared by spezyme and optidex. J. Ginseng Res. 38: 264-269.
    Pubmed KoreaMed CrossRef
  8. Chi H, Kim DH, Ji GE. 2005. Transformation of ginsenosides Rb2 and Rc from Panax ginseng by food microorganisms. Biol. Pharm. Bull. 28: 2102-2105.
    Pubmed CrossRef
  9. Quan K, Liu Q, Wan JY, Zhao YJ, Guo RZ, Alolga RN, et al. 2015. Rapid preparation of rare ginsenosides by acid transformation and their structure-activity relationships against cancer cells. Sci. Rep. 5: 8598.
    Pubmed KoreaMed CrossRef
  10. Tang XP, Tang GD, Fang CY, Liang ZH, Zhang LY. 2013. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J. Gastroenterol. 19: 1582-1592.
    Pubmed KoreaMed CrossRef
  11. Xia T, Wang JC, Xu W, Xu LH, Lao CH, Ye QX, et al. 2014. 20(S)-Ginsenoside Rh2 induces apoptosis in human leukaemia Reh cells through mitochondrial signaling pathways. Biol. Pharm. Bull. 37: 248-254.
    Pubmed CrossRef
  12. Guo XX, Li Y, Sun C, Jiang D, Lin YJ, Jin FX, et al. 2014. p53-dependent Fas expression is critical for ginsenoside Rh2 triggered caspase-8 activation in HeLa cells. Protein Cell 5: 224-234.
    Pubmed KoreaMed CrossRef
  13. Shi Q, Li J, Feng Z, Zhao L, Luo L, You Z, et al. 2014. Effect of ginsenoside Rh2 on the migratory ability of HepG2 liver carcinoma cells: recruiting histone deacetylase and inhibiting activator protein 1 transcription factors. Mol. Med. Rep. 10: 1779-1785.
    CrossRef
  14. Yang Z, Zhao T, Liu H, Zhang L. 2016. Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy. Sci. Rep. 6: 19383.
    Pubmed KoreaMed CrossRef
  15. Tung NH, Song GY, Minh CV, Kiem PV, Jin LG, Boo HJ, et al. 2010. Steamed ginseng-leaf components enhance cytotoxic effects on human leukemia HL-60 cells. Chem. Pharm Bull. 58: 1111-1115.
    CrossRef
  16. Vinoth Kumar R, Oh TW, Park YK. 2016. Anti-inflammatory effects of ginsenoside-Rh2 inhibits LPS-induced activation of microglia and overproduction of inflammatory mediators via modulation of TGF-beta1/Smad pathway. Neurochem. Res. 41: 951-957.
    Pubmed CrossRef
  17. Hwang JT, Kim SH, Lee MS, Kim SH, Yang HJ, Kim MJ, et al. 2007. Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. Biochem. Biophys. Res. Commun. 364: 1002-1008.
    Pubmed CrossRef
  18. Hou J, Xue J, Wang C, Liu L, Zhang D, Wang Z, et al. 2012. Microbial transformation of ginsenoside Rg3 to ginsenoside Rh2 by Esteya vermicola CNU 120806. World J. Microbiol. Biotechnol. 28: 1807-1811.
    Pubmed CrossRef
  19. 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. Pharm. Res. 27: 61-67.
    Pubmed CrossRef
  20. Kim JK, Cui CH, Liu Q, Yoon MH, Kim SC, Im WT. 2013. Mass production of the ginsenoside Rg3(S) through the combinative use of two glycoside hydrolases. Food Chem. 141: 1369-1377.
    Pubmed CrossRef
  21. Cui CH, Kim JK, Kim SC, Im WT. 2014. Characterization of a ginsenoside-transforming β-glucosidase from Paenibacillus mucilaginosus and its application for enhanced production of minor ginsenoside F2. PLoS One 9: e85727.
    Pubmed KoreaMed CrossRef
  22. Du J, Cui CH, Park SC, Kim JK, Yu HS, Jin FX, et al. 2014. Identification and characterization of a ginsenoside-transforming β-glucosidase from Pseudonocardia sp. Gsoil 1536 and its application for enhanced production of minor ginsenoside Rg2(S). PLoS One 9: e96914.
    Pubmed KoreaMed CrossRef
  23. Cui CH, Liu QM, Kim JK, Sung BH, Kim SG, Kim SC, et al. 2013. Identification and characterization of a Mucilaginibacter sp. strain QM49 β-glucosidase and its use in the production of the pharmaceutically active minor ginsenosides (S)-Rh1 and (S)-Rg2. Appl. Environ. Microbiol. 79: 5788-5798.
    Pubmed KoreaMed CrossRef
  24. Liu J, Shiono J, Shimizu K, Yu H, Zhang C, Jin F, et al. 2009. 20(R)-Ginsenoside Rh2, not 20(S), is a selective osteoclastgenesis inhibitor without any cytotoxicity. Bioorg. Med. Chem. Lett. 19: 3320-3323.
    Pubmed CrossRef
  25. Liu J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R. 2010. Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia 81: 902-905.
    Pubmed CrossRef
  26. Shi J, Cao B, Zha WB, Wu XL, Liu LS, Xiao WJ, et al. 2013. Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo. Acta Pharmacol. Sin. 34: 1349-1358.
    Pubmed KoreaMed CrossRef
  27. Quan LH, Jin Y, Wang C, Min JW, Kim YJ, Yang DC. 2012. Enzymatic transformation of the major ginsenoside Rb2 to minor compound Y and compound K by a ginsenosidehydrolyzing β-glycosidase from Microbacterium esteraromaticum. J. Ind. Microbiol. Biotechnol. 39: 1557-1562.
    Pubmed CrossRef