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Planta Med 2018; 84(11): 813-819
DOI: 10.1055/s-0044-102099
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Impact of Green Tea Catechin ECG and Its Synthesized Fluorinated Analogue on Prostate Cancer Cells and Stimulated Immunocompetent Cells

Sven Stadlbauer
1   Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Carmen Steinborn
1   Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Amy Klemd
1   Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Fumihiko Hattori
2   Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, Japan
,
Ken Ohmori
2   Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, Japan
,
Keisuke Suzuki
2   Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, Japan
,
Roman Huber
1   Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Philipp Wolf
3   Department of Urology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Carsten Gründemann
1   Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
› Author Affiliations
Further Information

Publication History

received 15 December 2017
revised 11 January 2018

accepted 26 January 2018

Publication Date:
21 February 2018 (online)

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Abstract

Among the known or suspected risk factors, inflammation plays an important role in infectious and non-infectious pathways leading to cancer. Green tea polyphenols have been associated with reducing inflammation and protection against carcinogenesis, especially in prostate cancer. While most of the research in this field, so far, has focussed on epigallocatechin-3-O-gallate only, we studied epicatechin-3-O-gallate, the second most abundant green tea polyphenol with essential therapeutic potential, to obtain a more detailed understanding of its anti-tumor and anti-inflammatory action. Furthermore, to improve the bioactivity of (−)-epicatechin-3-O-gallate, we synthesized a difluoro analogue, called (−)-5,7-difluoro-epicatechin-3-O-gallate. Both compounds reduced cell proliferation of human primary inflammatory lymphocytes in an apoptosis-specific fashion, while (−)-5,7-difluoro-epicatechin-3-O-gallate had a significantly higher activity compared to the natural product (−)-epicatechin-3-O-gallate. Treatment of low-metastatic LNCaP and high-metastatic PC-3 prostate cancer cells with (−)-epicatechin-3-O-gallate and (−)-5,7-difluoro-epicatechin-3-O-gallate demonstrated a dose-dependent inhibition of cell viability in the low micromolar range. These effects suggest that (−)-epicatechin-3-O-gallate and the more effective (−)-5,7-difluoro-epicatechin-3-O-gallate could be therapeutically used to inhibit tumorigenesis during initiation, promotion, and progression by diminishing the amount of inflammation due to a reduction of inflammatory lymphocytes. Further studies are needed to prove this in in vivo experiments.

Key words

Camellia sinensis - Theaceae - green tea polyphenols - fluorine analogue - prostate cancer - inflammation

Supporting Information

    The detailed synthetic procedures for the fluorinated ECG analogue are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359-E386
    CrossrefPubMedGoogle Scholar
  • 2 Galletti G, Leach BI, Lam L, Tagawa ST. Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer. Cancer Treat Rev 2017; 57: 16-27
    CrossrefPubMedGoogle Scholar
  • 3 Kimura T. East meets West: ethnic differences in prostate cancer epidemiology between East Asians and Caucasians. Chin J Cancer 2012; 31: 421-429
    CrossrefPubMedGoogle Scholar
  • 4 Kurotani K, Akter S, Kashino I, Goto A, Mizoue T, Noda M, Sasazuki S, Sawada N, Tsugane S. Quality of diet and mortality among Japanese men and women: Japan Public Health Center based prospective study. BMJ 2016; 352: i1209
    PubMedGoogle Scholar
  • 5 Kurahashi N, Sasazuki S, Iwasaki M, Inoue M. Green tea consumption and prostate cancer risk in Japanese men: a prospective study. Am J Epidemiol 2008; 167: 71-77
    PubMedGoogle Scholar
  • 6 Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 2008; 54: 472-473
    CrossrefPubMedGoogle Scholar
  • 7 Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 2006; 66: 1234-1240
    CrossrefPubMedGoogle Scholar
  • 8 Juneja LR, Kapoor MP, Okuba T, Rao TP. Green Tea Polyphenols. Boca Raton: CRC Press; 2013
    Google Scholar
  • 9 Hara Y. Green Tea: Health Benefits and Applications. Boca Raton: CRC Press; 2001
    Google Scholar
  • 10 Nakayama M, Suzuki K, Toda M, Okubo S, Hara Y, Shimamura T. Inhibition of the infectivity of influenza virus by tea polyphenols. Antiviral Res 1993; 21: 289-299
    CrossrefPubMedGoogle Scholar
  • 11 Song JM, Lee KH, Seong BL. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 2005; 68: 66-74
    CrossrefPubMedGoogle Scholar
  • 12 Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997; 89: 1881-1886
    CrossrefPubMedGoogle Scholar
  • 13 Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate. Cancer Res 2006; 66: 2500-2505
    CrossrefPubMedGoogle Scholar
  • 14 Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci 2001; 98: 10350-10355
    CrossrefPubMedGoogle Scholar
  • 15 Siddiqui IA, Asim M, Hafeez BB, Adhami VM, Tarapore RS, Mukhtar H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB J 2011; 25: 1198-1207
    CrossrefPubMedGoogle Scholar
  • 16 Li Y, Chang SC, Goldstein BY, Scheider WL, Cai L, You NC, Tarleton HP, Ding B, Zhao J, Wu M, Jiang Q, Yu S, Rao J, Lu QY, Zhang ZF, Mu L. Green tea consumption, inflammation and the risk of primary hepatocellular carcinoma in a Chinese population. Cancer Epidemiol 2011; 35: 362-368
    CrossrefPubMedGoogle Scholar
  • 17 Kim HS, Quon MJ, Kim JA. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol 2014; 2: 187-195
    CrossrefPubMedGoogle Scholar
  • 18 Lambert JD, Elias RJ. The antioxidant and pro-oxidant activities of green tea polyphenols: a role in cancer prevention. Arch Biochem Biophys 2010; 501: 65-72
    CrossrefPubMedGoogle Scholar
  • 19 Butt MS, Ahmad RS, Sultan MT, Qayyum MMN, Naz A. Green tea and anticancer perspectives: updates from last decade. Critical Rev Food Sci Nutr 2015; 55: 792-805
    CrossrefPubMedGoogle Scholar
  • 20 Fechtner S, Singh A, Chourasia M, Ahmed S. Molecular insights into the differences in anti-inflammatory activities of green tea catechins on IL-1β signaling in rheumatoid arthritis synovial fibroblasts. Toxicol Appl Pharmacol 2017; 329: 112-120
    CrossrefPubMedGoogle Scholar
  • 21 Fan FY, Sang LX, Jiang M. Catechins and their therapeutic benefits to inflammatory bowel disease. Molecules 2017; 22: E484
    CrossrefPubMedGoogle Scholar
  • 22 Molina N, Bolin AP, Otton R. Green tea polyphenols change the profile of inflammatory cytokine release from lymphocytes of obese and lean rats and protect against oxidative damage. Internat Immunopharmacol 2015; 28: 985-996
    PubMedGoogle Scholar
  • 23 Hu Y, McIntosh GH, Le Leu RK, Somashekar R, Meng XQ, Gopalsamy G, Bambaca L, McKinnon RA, Young GP. Supplementation with Brazil nuts and green tea extract regulates targeted biomarkers related to colorectal cancer risk in humans. Br J Nutr 2016; 116: 1901-1911
    CrossrefPubMedGoogle Scholar
  • 24 Dunitz JD. Organic fluorine: odd man out. Chembiochem 2004; 5: 614-621
    CrossrefPubMedGoogle Scholar
  • 25 Biffinger JC, Kim HW, DiMagno SG. The polar hydrophobicity of fluorinated compounds. Chembiochem 2004; 5: 622-627
    CrossrefPubMedGoogle Scholar
  • 26 Böhm HJ, Banner D, Bendels S, Kansy M, Kuhn B, Müller K, Obst-Sander U, Stahl M. Fluorine in medicinal chemistry. Chembiochem 2004; 5: 637-643
    CrossrefPubMedGoogle Scholar
  • 27 Britton RG, Horner-Glister E, Pomenya OA, Smith EE, Denton R, Jenkins PR, Steward WP, Brown K, Gescher A, Sale S. Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents. Eur J Med Chem 2012; 54: 952-958
    CrossrefPubMedGoogle Scholar
  • 28 Dias TA, Duarte CL, Lima CF, Proença MF, Pereira-Wilson C. Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin. Eur J Med Chem 2013; 65: 500-510
    CrossrefPubMedGoogle Scholar
  • 29 Stadlbauer S, Rios P, Ohmori K, Suzuki K, Köhn M. Procyanidins negatively affect the activity of the phosphatases of regenerating liver. PLoS One 2015; 10: e0134336
    CrossrefPubMedGoogle Scholar
  • 30 Ohmori K, Yano T, Suzuki K. General synthesis of epi-series catechins and their 3-gallates: reverse polarity strategy. Org Biomol Chem 2010; 8: 2693-2696
    CrossrefPubMedGoogle Scholar
  • 31 Swallow S. Fluorine in medicinal Chemistry. In: Progress in medicinal Chemistry, Vol. 54. Elsevier; 2015: 65-133
    Google Scholar
  • 32 Müller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007; 317: 1881-1886
    CrossrefPubMedGoogle Scholar
  • 33 Akbar AN, Salmon M. Cellular environments and apoptosis: tissue microenvironments control activated T-cell death. Immunol Today 1997; 18: 72-76
    CrossrefPubMedGoogle Scholar
  • 34 Buckley CD. Why does chronic inflammatory joint disease persist. Clin Med 2003; 3: 361-366
    CrossrefPubMedGoogle Scholar
  • 35 Stadlbauer S, Hattori F, Ohmori K, Suzuki K. A new synthetic strategy for catechin-class polyphenols: concise synthesis of (−)-epicatechin and its 3-O-gallate. Chem Commun 2012; 48: 8425-8427
    CrossrefPubMedGoogle Scholar