DOI QR코드

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Inhibitory Aromatase Effects of Flavonoids from Ginkgo Biloba Extracts on Estrogen Biosynthesis

  • Park, Yong Joo ;
  • Choo, Wun Hak ;
  • Kim, Ha Ryong ;
  • Chung, Kyu Hyuck ;
  • Oh, Seung Min
  • Published : 2015.10.06

Abstract

Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion.

Keywords

Aromatase;estrogen biosynthesis;breast cancer;flavonoids;ginkgo biloba extracts

References

  1. Adlercreutz H (1995). Phytoestrogens: epidemiology and a possible role in cancer protection. Environ Health Perspect, 103, 103-12. https://doi.org/10.1289/ehp.95103s2103
  2. Bahadoran Z, Karimi Z, Houshiar-rad A, et al (2013). Dietary phytochemical index and the risk of breast cancer: a case control study in a population of Iranian women. Asian Pac J Cancer Prev, 14, 2747-51. https://doi.org/10.7314/APJCP.2013.14.5.2747
  3. Balunas MJ, Kinghorn AD (2010). Natural compounds with aromatase inhibitory activity: an update. Planta Med, 76, 1087-93. https://doi.org/10.1055/s-0030-1250169
  4. Behan LA, Amir E, Casper RF (2015). Aromatase inhibitors for prevention of breast cancer in postmenopausal women: a narrative review. Menopause, 22, 342-50. https://doi.org/10.1097/GME.0000000000000426
  5. Bernstein L, Ross RK (1993). Endogenous hormones and breast cancer risk. Epidemiol Rev, 15, 48-65.
  6. Brueggemeier RW, Hackett JC, Diaz-Cruz ES (2005). Aromatase inhibitors in the treatment of breast cancer. Endocr Rev, 26, 331-45. https://doi.org/10.1210/er.2004-0015
  7. Bulun SE, Sebastian S, Takayama K, et al (2003). The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol, 86, 219-24. https://doi.org/10.1016/S0960-0760(03)00359-5
  8. Cazzaniga M, Bonanni B (2012). Breast cancer chemoprevention: old and new approaches. J Biomed Biotechnol, 2012, 985620.
  9. Chen S, Oh SR, Phung S, et al (2006). Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus). Cancer Res, 66, 12026-34. https://doi.org/10.1158/0008-5472.CAN-06-2206
  10. Chumsri S, Howes T, Bao T, et al (2011). Aromatase, aromatase inhibitors, and breast cancer. J Steroid Biochem Mol Biol, 125, 13-22. https://doi.org/10.1016/j.jsbmb.2011.02.001
  11. Cieza A, Maier P, Poppel E (2003). Effects of Ginkgo biloba on mental functioning in healthy volunteers. Arch of Med Res, 34, 373-81. https://doi.org/10.1016/j.arcmed.2003.05.001
  12. Dubber MJ, Kanfer I (2004). High-performance liquid chromatographic determination of selected flavonols in Ginkgo biloba solid oral dosage forms. J Pharm Pharm Sci, 7, 303-9.
  13. Eng ET, Ye J, Williams D, et al (2003). Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds. Cancer Res, 63, 8516-22.
  14. Harada N, Utsumi T, Takagi Y (1993). Tissue-specific expression of the human aromatase cytochrome P-450 gene by alternative use of multiple exons 1 and promoters, and switching of tissue-specific exons 1 in carcinogenesis. Proc Natl Acad Sci U S A, 90, 11312-6. https://doi.org/10.1073/pnas.90.23.11312
  15. Hong Y, Chen S (2006). Aromatase inhibitors: structural features and biochemical characterization. Ann N Y Acad Sci, 1089, 237-51. https://doi.org/10.1196/annals.1386.022
  16. Huang SM, Temple R, Throckmorton DC, et al (2007). Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther, 81, 298-304. https://doi.org/10.1038/sj.clpt.6100054
  17. Iwase H, Yamamoto Y (2015). Clinical benefit of sequential use of endocrine therapies for metastatic breast cancer. Int J Clin Oncol, 20, 253-61. https://doi.org/10.1007/s10147-015-0793-8
  18. Kamat A, Alcorn JL, Kunczt C, et al (1998). Characterization of the regulatory regions of the human aromatase (P450arom) gene involved in placenta-specific expression. Mol Endocrinol, 12, 1764-77. https://doi.org/10.1210/mend.12.11.0190
  19. Kellis JT, Jr., Vickery LE (1984). Inhibition of human estrogen synthetase (aromatase) by flavones. Science, 225, 1032-4. https://doi.org/10.1126/science.6474163
  20. Khan SI, Zhao J, Khan IA, et al (2011). Potential utility of natural products as regulators of breast cancer-associated aromatase promoters. Reprod Biol Endocrinol, 9, 91. https://doi.org/10.1186/1477-7827-9-91
  21. Kijima I, Phung S, Hur G, et al (2006). Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res, 66, 5960-7. https://doi.org/10.1158/0008-5472.CAN-06-0053
  22. Kim MJ, Park YJ, Chung KH, et al (2013). The inhibitory effects of the standardized extracts of ginkgo biloba on aromatase activity in JEG-3 human choriocarcinoma cells. phytother res.
  23. Kleijnen J, Knipschild P (1992). Ginkgo biloba. Lancet, 340, 1136-9. https://doi.org/10.1016/0140-6736(92)93158-J
  24. Kohler PO, Bridson WE (1971). Isolation of hormoneproducing clonal lines of human choriocarcinoma. J Clin Endocrinol Metab, 32, 683-7. https://doi.org/10.1210/jcem-32-5-683
  25. Kudolo GB (2001). The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. J Clin Pharmacol, 41, 600-11. https://doi.org/10.1177/00912700122010483
  26. Kudolo GB, Delaney DJ (2001). The effect of the ingestion of Ginkgo biloba extract on platelet lipid peroxidation. Clin Chem, 47, 51.
  27. Lu DF, Yang LJ, Wang F, et al (2012). Inhibitory effect of luteolin on estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19). J Agric Food Chem, 60, 8411-8. https://doi.org/10.1021/jf3022817
  28. Mahmoud F, Abul H, Onadeko B, et al (2000). In vitro effects of Ginkgolide B on lymphocyte activation in atopic asthma: Comparison with cyclosporin A. Japanese J Pharmacol, 83, 241-5. https://doi.org/10.1254/jjp.83.241
  29. Meiyanto E, Hermawan A, Anindyajati (2012). Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev, 13, 427-36. https://doi.org/10.7314/APJCP.2012.13.2.427
  30. Monteiro R, Azevedo I, Calhau C (2006). Modulation of aromatase activity by diet polyphenolic compounds. J Agric Food Chem, 54, 3535-40. https://doi.org/10.1021/jf053237t
  31. Mu YM, Yanase T, Nishi Y, et al (2000). A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells. Mol Cell Endocrinol, 166, 137-45. https://doi.org/10.1016/S0303-7207(00)00273-2
  32. Mukhopadhyay K, Liu Z, Bandyopadhyay A, et al (2015). Aromatase Expression Increases the Survival and Malignancy of Estrogen Receptor Positive Breast Cancer Cells. PLoS One, 10, 121136.
  33. Oh SM, Chung KH (2004). Estrogenic activities of Ginkgo biloba extracts. Life Sci, 74, 1325-35. https://doi.org/10.1016/j.lfs.2003.06.045
  34. Oh SM, Chung KH (2006). Antiestrogenic activities of Ginkgo biloba extracts. J Steroid Biochem Mol Biol, 100, 167-76. https://doi.org/10.1016/j.jsbmb.2006.04.007
  35. Oh SM, Kim HR, Chung KH (2008). Effects of ginkgo biloba on in vitro osteoblast cells and ovariectomized rat osteoclast cells. Arch Pharm Res, 31, 216-24. https://doi.org/10.1007/s12272-001-1144-z
  36. Perez P, Pulgar R, Olea-Serrano F, et al (1998). The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups. Environ Health Perspect, 106, 167-74. https://doi.org/10.1289/ehp.98106167
  37. Plant N (2004). Strategies for using in vitro screens in drug metabolism. Drug Discov Today, 9, 328-36. https://doi.org/10.1016/S1359-6446(03)03019-8
  38. Renoir JM, Marsaud V, Lazennec G (2012). Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol.
  39. Rigney U, Kimber S, Hindmarch I (1999). The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytother Res, 13, 408-15. https://doi.org/10.1002/(SICI)1099-1573(199908/09)13:5<408::AID-PTR530>3.0.CO;2-C
  40. Saarinen N, Joshi SC, Ahotupa M, et al (2001). No evidence for the in vivo activity of aromataseinhibiting flavonoids. J Steroid Biochem Mol Biol, 78, 231-9. https://doi.org/10.1016/S0960-0760(01)00098-X
  41. Suganya J, Radha M, Naorem DL, et al (2014). In Silico docking studies of selected flavonoids--natural healing agents against breast cancer. Asian Pac J Cancer Prev, 15, 8155-9. https://doi.org/10.7314/APJCP.2014.15.19.8155
  42. To SQ, Knower KC, Cheung V, et al (2015). Transcriptional control of local estrogen formation by aromatase in the breast. J Steroid Biochem Mol Biol, 145, 179-86. https://doi.org/10.1016/j.jsbmb.2014.05.004
  43. Wang Y, Lee KW, Chan FL, et al (2006). The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci, 92, 71-7. https://doi.org/10.1093/toxsci/kfj190
  44. Yager JD, Davidson NE (2006). Estrogen carcinogenesis in breast cancer. N Engl J Med, 354, 270-82. https://doi.org/10.1056/NEJMra050776
  45. Yue W, Brodie AM (1997). Mechanisms of the actions of aromatase inhibitors 4-hydroxyandrostenedione, fadrozole, and aminoglutethimide on aromatase in JEG-3 cell culture. J Steroid Biochem Mol Biol, 63, 317-28. https://doi.org/10.1016/S0960-0760(97)00072-1

Cited by

  1. The effects of the standardized extracts of Ginkgo biloba on steroidogenesis pathways and aromatase activity in H295R human adrenocortical carcinoma cells vol.31, pp.2233-6567, 2016, https://doi.org/10.5620/eht.e2016010
  2. Leaves Extract (EGb 761) by a Validated UPLC–MS-MS Method pp.1945-239X, 2017, https://doi.org/10.1093/chromsci/bmw206

Acknowledgement

Supported by : National Research Foundation of Korea