Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginseng berry polysaccharides on inflammation-associated colon cancer: inhibiting T-cell differentiation, promoting apoptosis, and enhancing the effects of 5-fluorouracil

  • Wang, Chong-Zhi (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Hou, Lifei (Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School) ;
  • Wan, Jin-Yi (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Yao, Haiqiang (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Yuan, Jinbin (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Zeng, Jinxiang (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Park, Chan Woong (Vital Beautie Research Institute, R&D Center, AmorePacific Corporation) ;
  • Kim, Su Hwan (Vital Beautie Research Institute, R&D Center, AmorePacific Corporation) ;
  • Seo, Dae Bang (Vital Beautie Research Institute, R&D Center, AmorePacific Corporation) ;
  • Shin, Kwang-Soon (Department of Food Science and Biotechnology, Kyonggi University) ;
  • Zhang, Chun-Feng (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Chen, Lina (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Zhang, Qi-Hui (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Liu, Zhi (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Sava-Segal, Clara (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago) ;
  • Yuan, Chun-Su (Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago)
  • Received : 2018.05.03
  • Accepted : 2018.12.26
  • Published : 2020.03.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms. Methods: Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation. Results: GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4+IFN-γ+ cell (Th1) differentiation, and decreased CD4+FoxP3+ cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil. Conclusion: Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms.

Keywords

References

  1. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  2. Cui S, Wu J, Wang J, Wang X. Discrimination of American ginseng and Asian ginseng using electronic nose and gas chromatography-mass spectrometry coupled with chemometrics. J Ginseng Res 2017;41:85-95. https://doi.org/10.1016/j.jgr.2016.01.002
  3. Dai D, Zhang CF, Williams S, Yuan CS, Wang CZ. Ginseng on cancer: potential role in modulating inflammation-mediated angiogenesis. Am J Chin Med 2017;45:13-22. https://doi.org/10.1142/s0192415x17500021
  4. Yun TK, Choi SY. Preventive effect of ginseng intake against various human cancers: a case-control study on 1987 pairs. Cancer Epidemiol Biomarkers Prev 1995;4:401-8.
  5. Yun TK. Panax ginseng - a non-organ-specific cancer preventive? Lancet Oncol 2001;2:49-55. https://doi.org/10.1016/s1470-2045(00)00196-0
  6. Park J, Bui PTC, Song H, Kim SK, Rhee DK, Kim EY, Rhyu MR, Lee MS, Lee YJ. Ginseng on nuclear hormone receptors. Am J Chin Med 2017;45:1147-56. https://doi.org/10.1142/s0192415x17500628
  7. Yu C, Wen XD, Zhang Z, Zhang CF, Wu X, He X, Liao Y, Wu N, Wang CZ, Du W, et al. American ginseng significantly reduced the progression of high-fat-dietenhanced colon carcinogenesis in Apc (Min/+) mice. J Ginseng Res 2015;39:230-7. https://doi.org/10.1016/j.jgr.2014.12.004
  8. Yu C, Wen XD, Zhang Z, Zhang CF, Wu XH, Martin A, Du W, He TC, Wang CZ, Yuan CS. American ginseng attenuates azoxymethane/dextran sodium sulfateinduced colon carcinogenesis in mice. J Ginseng Res 2015;39:14-21. https://doi.org/10.1016/j.jgr.2014.07.001
  9. Wang CZ, Yu C, Wen XD, Chen L, Zhang CF, Calway T, Qiu Y, Wang Y, Zhang Z, Anderson S, et al. American ginseng attenuates colitis-associated colon carcinogenesis in mice: impact on gut microbiota and metabolomics. Cancer Prev Res (Phila) 2016;9:803-11. https://doi.org/10.1158/1940-6207.CAPR-15-0372
  10. Wang CZ, Huang WH, Zhang CF, Wan JY, Wang Y, Yu C, Williams S, He TC, Du W, Musch MW, et al. Role of intestinal microbiome in American ginsengmediated colon cancer prevention in high fat diet-fed AOM/DSS mice. Clin Transl Oncol 2018;20:302-12. https://doi.org/10.1007/s12094-017-1717-z
  11. Foersch S, Waldner MJ, Neurath MF. Colitis and colorectal cancer. Dig Dis 2012;30:469-76. https://doi.org/10.1159/000341692
  12. McCarthy N. Tumorigenesis: all together now. Nat Rev Cancer 2013;13:148. https://doi.org/10.1038/nrc3469
  13. Nishitani Y, Zhang L, Yoshida M, Azuma T, Kanazawa K, Hashimoto T, Mizuno M. Intestinal anti-inflammatory activity of lentinan: influence on IL-8 and TNFR1 expression in intestinal epithelial cells. PLoS One 2013;8:e62441. https://doi.org/10.1371/journal.pone.0062441
  14. Madka V, Rao CV. Anti-inflammatory phytochemicals for chemoprevention of colon cancer. Curr Cancer Drug Targets 2013;13:542-57. https://doi.org/10.2174/15680096113139990036
  15. Khan R, Khan AQ, Lateef A, Rehman MU, Tahir M, Ali F, Hamiza OO, Sultana S. Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. PLoS One 2013;8:e56020. https://doi.org/10.1371/journal.pone.0056020
  16. Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med 2002;8:567-73. https://doi.org/10.1038/nm0602-567
  17. Lewis B, Lin J, Wu X, Xie H, Shen B, Lai K, Manilich E, Liu X. Crohn's disease-like reaction predicts favorable prognosis in colitis-associated colorectal cancer. Inflamm Bowel Dis 2013;19:2190-8. https://doi.org/10.1097/MIB.0b013e31829e13e1
  18. Matsuoka K, Inoue N, Sato T, Okamoto S, Hisamatsu T, Kishi Y, Sakuraba A, Hitotsumatsu O, Ogata H, Koganei K, et al. T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease. Gut 2004;53:1303-8. https://doi.org/10.1136/gut.2003.024190
  19. Saigusa K, Hisamatsu T, Handa T, Sujino T, Mikami Y, Hayashi A, Mizuno S, Takeshita K, Sato T, Matsuoka K, et al. Classical Th1 cells obtain colitogenicity by co-existence of RORgammat-expressing T cells in experimental colitis. Inflamm Bowel Dis 2014;20:1820-7. https://doi.org/10.1097/MIB.0000000000000149
  20. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest 2007;117:1167-74. https://doi.org/10.1172/JCI31202
  21. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011;105:93-103. https://doi.org/10.1038/bjc.2011.189
  22. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol 2013;171:36-45. https://doi.org/10.1111/j.1365-2249.2012.04657.x
  23. Qi Y, Gao F, Hou L, Wan C. Anti-inflammatory and immunostimulatory activities of astragalosides. Am J Chin Med 2017;45:1157-67. https://doi.org/10.1142/s0192415x1750063x
  24. Qi LW, Wang CZ, Yuan CS. American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol 2010;80:947-54. https://doi.org/10.1016/j.bcp.2010.06.023
  25. Wang L, Yu X, Yang X, Li Y, Yao Y, Lui EM, Ren G. Structural and antiinflammatory characterization of a novel neutral polysaccharide from North American ginseng (Panax quinquefolius). Int J Biol Macromol 2015;74:12-7. https://doi.org/10.1016/j.ijbiomac.2014.10.062
  26. Khan MSA, Khundmiri SUK, Khundmiri SR, Al-Sanea MM, Mok PL. Fruitderived polysaccharides and terpenoids: recent update on the gastroprotective effects and mechanisms. Front Pharmacol 2018;9:569. https://doi.org/10.3389/fphar.2018.00569
  27. Li XL, Wang CZ, Mehendale SR, Sun S, Wang Q, Yuan CS. Panaxadiol, a purified ginseng component, enhances the anti-cancer effects of 5-fluorouracil in human colorectal cancer cells. Cancer Chemother Pharmacol 2009;64:1097-104. https://doi.org/10.1007/s00280-009-0966-0
  28. Fishbein AB, Wang CZ, Li XL, Mehendale SR, Sun S, Aung HH, Yuan CS. Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng. Arch Pharm Res 2009;32:505-13. https://doi.org/10.1007/s12272-009-1405-9
  29. Wan JY, Huang WH, Zheng W, Park CW, Kim SH, Seo DB, Shin KS, Zeng J, Yao H, Sava-Segal C, et al. Multiple effects of ginseng berry polysaccharides: plasma cholesterol level reduction and enteric neoplasm prevention. Am J Chin Med 2017;45:1293-307. https://doi.org/10.1142/S0192415X17500719
  30. Mazzucchelli L, Hauser C, Zgraggen K, Wagner H, Hess M, Laissue JA, Mueller C. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol 1994;144:997-1007.
  31. Garcia Rodriguez LA, Cea-Soriano L, Tacconelli S, Patrignani P. Coxibs: pharmacology, toxicity and efficacy in cancer clinical trials. Recent Results Cancer Res 2013;191:67-93. https://doi.org/10.1007/978-3-642-30331-9_4
  32. Bao J, Ding RB, Liang Y, Liu F, Wang K, Jia X, Zhang C, Chen M, Li P, Su H, et al. Differences in chemical component and anticancer activity of green and ripe Forsythiae Fructus. Am J Chin Med 2017;45:1513-36. https://doi.org/10.1142/S0192415X17500823
  33. Tien AJ, Chien CY, Chen YH, Lin LC, Chien CT. Fruiting bodies of Antrodia cinnamomea and its active triterpenoid, antcin K, ameliorates N-nitrosodiethylamine-induced hepatic inflammation, fibrosis and carcinogenesis in rats. Am J Chin Med 2017;45:173-98. https://doi.org/10.1142/s0192415x17500124
  34. Wang L, Yao Y, Sang W, Yang X, Ren G. Structural features and immunostimulating effects of three acidic polysaccharides isolated from Panax quinquefolius. Int J Biol Macromol 2015;80:77-86. https://doi.org/10.1016/j.ijbiomac.2015.06.007
  35. Muzes G, Molnar B, Tulassay Z, Sipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol 2012;18:5848-61. https://doi.org/10.3748/wjg.v18.i41.5848
  36. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 2017;4:33-46. https://doi.org/10.1016/j.jcmgh.2017.03.007
  37. Monteleone I, Vavassori P, Biancone L, Monteleone G, Pallone F. Immunoregulation in the gut: success and failures in human disease. Gut 2002;50(Suppl. 3):III60-64.
  38. Kanai T, Watanabe M, Okazawa A, Sato T, Yamazaki M, Okamoto S, Ishii H, Totsuka T, Iiyama R, Okamoto R, et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. Gastroenterology 2001;121:875-88. https://doi.org/10.1053/gast.2001.28021
  39. Bosani M, Ardizzone S, Porro GB. Biologic targeting in the treatment of inflammatory bowel diseases. Biologics 2009;3:77-97.
  40. Loh SH, Park JY, Cho EH, Nah SY, Kang YS. Animal lectins: potential receptors for ginseng polysaccharides. J Ginseng Res 2017;41:1-9. https://doi.org/10.1016/j.jgr.2015.12.006
  41. Yuan LB, Hua CY, Gao S, Yin YL, Dai M, Meng HY, Li PP, Yang ZX, Hu QH. Astragalus polysaccharides attenuate monocrotaline-induced pulmonary arterial hypertension in rats. Am J Chin Med 2017;45:773-89. https://doi.org/10.1142/S0192415X17500410
  42. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Canellas A, Hernando-Momblona X, et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554:538-43. https://doi.org/10.1038/nature25492
  43. Whiteside TL, Mandapathil M, Szczepanski M, Szajnik M. Mechanisms of tumor escape from the immune system: adenosine-producing Treg, exosomes and tumor-associated TLRs. Bull Cancer 2011;98:E25-31. https://doi.org/10.1684/bdc.2010.1294
  44. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307. https://doi.org/10.1038/nri1806

Cited by

  1. Methanol Extract of Coleus amboinicus (Lour) Exhibited Antiproliferative Activity and Induced Programmed Cell Death in Colon Cancer Cell WiDr vol.2020, 2020, https://doi.org/10.1155/2020/9068326
  2. Impact of Qi-Invigorating Traditional Chinese Medicines on Diffuse Large B Cell Lymphoma Based on Network Pharmacology and Experimental Validation vol.12, 2020, https://doi.org/10.3389/fphar.2021.787816
  3. Strategies for Remodeling the Tumor Microenvironment Using Active Ingredients of Ginseng-A Promising Approach for Cancer Therapy vol.12, 2021, https://doi.org/10.3389/fphar.2021.797634
  4. Recent progress in polysaccharides from Panax ginseng C. A. Meyer vol.12, pp.2, 2020, https://doi.org/10.1039/d0fo01896a
  5. Comparisons of Isolation Methods, Structural Features, and Bioactivities of the Polysaccharides from Three Common Panax Species: A Review of Recent Progress vol.26, pp.16, 2021, https://doi.org/10.3390/molecules26164997
  6. Pharmacological properties of ginsenosides in inflammation-derived cancers vol.476, pp.9, 2021, https://doi.org/10.1007/s11010-021-04162-w
  7. Ginseng root extract attenuates inflammation by inhibiting the MAPK/NF-κB signaling pathway and activating autophagy and p62-Nrf2-Keap1 signaling in vitro and in vivo vol.283, 2022, https://doi.org/10.1016/j.jep.2021.114739