Hormones and Cancer

, Volume 4, Issue 5, pp 293–300 | Cite as

Endocrine Disrupting Activities of the Flavonoid Nutraceuticals Luteolin and Quercetin

  • Steven K. Nordeen
  • Betty J. Bona
  • David N. Jones
  • James R. Lambert
  • Twila A. Jackson
Original Paper

Abstract

Dietary plant flavonoids have been proposed to contribute to cancer prevention, neuroprotection, and cardiovascular health through their anti-oxidant, anti-inflammatory, pro-apoptotic, and antiproliferative activities. As a consequence, flavonoid supplements are aggressively marketed by the nutraceutical industry for many purposes, including pediatric applications, despite inadequate understanding of their value and drawbacks. We show that two flavonoids, luteolin and quercetin, are promiscuous endocrine disruptors. These flavonoids display progesterone antagonist activity beneficial in a breast cancer model but deleterious in an endometrial cancer model. Concurrently, luteolin possesses potent estrogen agonist activity while quercetin is considerably less effective. These results highlight the promise and peril of flavonoid nutraceuticals and suggest caution in supplementation beyond levels attained in a healthy, plant-rich diet.

References

  1. 1.
    Ramos S (2002) Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res 52:507–526CrossRefGoogle Scholar
  2. 2.
    Zern Tosca L, Fernandez ML (2005) Cardioprotective effect of dietary polyphenols. J Nutr 135:2291–2294PubMedGoogle Scholar
  3. 3.
    Nijveldt RJ, van Nood E, van Hoorn DEC, Boelens PG, van Norren K, van Leeuwen PAM (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74:418–425PubMedGoogle Scholar
  4. 4.
    Seelinger G, Merfort I, Wölfle U, Schempp CM (2008) Anti-carcinogenic effects of the flavonoid luteolin. Molecules 13:2628–2651PubMedCrossRefGoogle Scholar
  5. 5.
    López-Lázaro M (2009) Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 9:31–59PubMedCrossRefGoogle Scholar
  6. 6.
    Press M, Groshen S, Kaminsky D, Hagerty M, Sherman L, Christensen K, Edwards DP (2002) Comparison of different antibodies for detection of progesterone receptor in breast cancer. Steroids 67:799–813PubMedCrossRefGoogle Scholar
  7. 7.
    Nordeen SK, Blanka K, Lawler-Heavner J, Barber DA, Edwards DP (1989) A quantitative comparison of dual control of a hormone response element by progestins and glucocorticoids in the same cell line. Mol Endocrinol 3:1270–1278PubMedCrossRefGoogle Scholar
  8. 8.
    Axlund SD, Yoo BH, Rosen RB, Schaack J, Kabos P, Barbera DV, Sartorius CA (2013) Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties. Horm Cancer 4:36–49PubMedCrossRefGoogle Scholar
  9. 9.
    Wilson VS, Kathy Bobseine L, Gray Jr. E (2004) Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 81:69–77Google Scholar
  10. 10.
    Ishiwata I, Ishiwata C, Soma M, Arai J, Ishikawa H (1984) Establishment of human endometrial adenocarcinoma cell line containing estradiol-17 beta and progesterone receptors. Gynecol Oncol 17:281–290PubMedCrossRefGoogle Scholar
  11. 11.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  12. 12.
    Krishan A (1975) Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining. J Cell Biol 66:188–193PubMedCrossRefGoogle Scholar
  13. 13.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461PubMedGoogle Scholar
  14. 14.
    Madauss KP, Grygielko ET, Deng S-J, Sulpizio AC, Stanley TB, Wu C, Short SA, Thompson SK, Stewart EL, Laping NJ, Williams SP, Bray JD (2007) A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Mol Endocrinol 21:1066–1081PubMedCrossRefGoogle Scholar
  15. 15.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791PubMedCrossRefGoogle Scholar
  16. 16.
    Aninye IO, Berg KC, Mollo AR, Nordeen SK, Wilson EM, Shapiro DJ (2012) 8-Alkylthio-6-thio-substituted theophylline analogues as selective progesterone receptor antagonists. Steroids 77:659–601CrossRefGoogle Scholar
  17. 17.
    Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovica A, Rohan TE, Yasmmen S, Prentice RL (2010) Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304:1684–1692PubMedCrossRefGoogle Scholar
  18. 18.
    Beral V, Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Woman Study. Lancet 362:419–427PubMedCrossRefGoogle Scholar
  19. 19.
    Kabos P, Haughian JM, Wang X, Dye WW, Finlayson C, Elias A, Horwitz KB, Sartorius CA (2011) Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat 128:45–55PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou P, Li L-P, Luo S-Q, Jiang H-D, Zeng S (2008) Intestinal absorption of luteolin from peanut hull extract is more efficient than that from individual pure luteolin. J Agric Food Chem 56:296–300Google Scholar
  21. 21.
    Shimoi K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, Hara Y, Yamamoto H, Kinae N (1998) Intestinal absorption of luteolin and luteolin 7-O-beta-glucoside in rats and humans. FEBS Lett 438:220–224PubMedCrossRefGoogle Scholar
  22. 22.
    Li L-P, Jiang H-D, Wu H, Zeng S (2005) Simultaneous determination of luteolin and apigenin in dog plamsa by RP-HPLC. J Pharm Biomed Anal 37:615–620Google Scholar
  23. 23.
    Moyer DL, Felix JC (1998) The effects of progesterone and progestins on endometrial proliferation. Contraception 57:399–403PubMedCrossRefGoogle Scholar
  24. 24.
    Felix JC, Farahmand S (1997) Endometrial glandular proliferation and estrogen receptor content during the normal menstrual cycle. Contraception 55:19–22PubMedCrossRefGoogle Scholar
  25. 25.
    Ferenczy A, Bertrand G, Gelfand MM (1979) Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol 133:859–867PubMedGoogle Scholar
  26. 26.
    Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS, Yamagishi H, Srivastava D, Bagchi MK, Bagchi IC (2011) The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331:912–916PubMedCrossRefGoogle Scholar
  27. 27.
    Xing N, Chen Y, Mitchell SH, Young CYF (2001) Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis 22:409–414PubMedCrossRefGoogle Scholar
  28. 28.
    Williams SP, Sigler PB (1998) Atomic structure of progesterone complexed with its receptor. Nature 393:392–396PubMedCrossRefGoogle Scholar
  29. 29.
    Raaijmakers HCA, Versteegh JE, Uitdehaag JCM (2009) The x-ray structure of RU486 bound to the progesterone receptor in a destabilized agonistic conformation. J Biol Chem 284:19572–19579PubMedCrossRefGoogle Scholar
  30. 30.
    Shutt DA (1976) The effects of plant estrogens on animal reproduction. Endeavour 35:110–113PubMedCrossRefGoogle Scholar
  31. 31.
    Livingston AL (1978) Forage plant estrogens. J Toxicol Environ Health 4:301–324PubMedCrossRefGoogle Scholar
  32. 32.
    Farnsworth NR, Bingel AS, Cordell GA, Crane FA, Fong HHS (1975) Potential value of plants as antifertility agents. II. J Pharm Sci 64:717–754PubMedCrossRefGoogle Scholar
  33. 33.
    Verdeal K, Ryan DS (1979) Naturally-occurring estrogens in plant foodstuffs: a review. J Food Prot 42:577–583Google Scholar
  34. 34.
    Martin PM, Horwitz KB, Ryan DS, McGuire WL (1978) Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103:1860–1867PubMedCrossRefGoogle Scholar
  35. 35.
    Farmakalidis EJ, Hathcock JN, Murphy PA (1985) Oestrogenic potency of genistein and daidzin in mice. J Food Prot 42:577–583Google Scholar
  36. 36.
    Miksicek RJ (1993) Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol 44:37–43PubMedGoogle Scholar
  37. 37.
    Le Bail JC, Varnat F, Nicolas JC, Habrioux G (1998) Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Lett 130:209–216Google Scholar
  38. 38.
    van der Woude H, ter Veld MGR, Jacobs N, van der Saag PT, Murk AJ, Rietjens IMCM (2005) The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res 49:763–771PubMedCrossRefGoogle Scholar
  39. 39.
    Ise R, Han D, Takahashi Y, Terasaka S, Inoue A, Tanji M, Kiyama R (2005) Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett 579:1732–1740PubMedCrossRefGoogle Scholar
  40. 40.
    Galluzzo P, Martini C, Bulzomi P, Leone S, Bolli A, Pallottini V, Marino M (2009) Quercetin-induced apoptotic cascade in cancer cells: antioxidant versus estrogen receptor α-dependent mechanisms. Mol Nutr Food Res 53:699–708PubMedCrossRefGoogle Scholar
  41. 41.
    Lin FM, Chen L-R, Lin E-H, Ke F-C, Chen H-Y, Tsai M-J, Hsiao P-W (2007) Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. Carcinogenesis 28:2521–2529PubMedCrossRefGoogle Scholar
  42. 42.
    Willemsen P, Scippo M-L, Kausel G, Figueroa J, Maghuin-Rogister G, Martial JA, Muller M (2004) Use of reporter cell lines for detection of endocrine-disrupter activity. Anal Bioanal Chem 378:655–663PubMedCrossRefGoogle Scholar
  43. 43.
    Scippo M-L, Argiris C, Van De Weerdt C, Muller M, Willemsen P, Martial J, Maghuin-Rogister G (2004) Recombinant human estrogen, androgen, and progesterone receptors for detection of potential endocrine disruptors. Anal Bioanal Chem 378:664–669PubMedCrossRefGoogle Scholar
  44. 44.
    Toh MF, Sohn J, Chen SN, Yao P, Bolton JL, Burdette JE (2012) Biological characterization of non-steroidal progestins from botanicals used for women’s health. Steroids 77:765–773PubMedCrossRefGoogle Scholar
  45. 45.
    Rosenberg RS, Grass L, Jenkins DJA, Kendall CWC, Diamandis EP (1998) Modulation of androgen and progesterone receptors by phytochemicals in breast cancer cell lines. Biochem Biophys Res Commun 248:935–939PubMedCrossRefGoogle Scholar
  46. 46.
    Mafuvadze B, Benakanakere I, López-Perez FR, Besch-Williford C, Ellersieck MR, Hyder SM (2011) Apigenin prevents development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague–Dawley rats. Cancer Prev Res 4:1316–1324Google Scholar
  47. 47.
    Mafuvadze B, Liang Y, Besch-Williford C, Zhang X, Hyder SM (2012) Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors. Horm Cancer 3:160–171Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Steven K. Nordeen
    • 1
  • Betty J. Bona
    • 1
  • David N. Jones
    • 2
  • James R. Lambert
    • 1
  • Twila A. Jackson
    • 3
  1. 1.Department of PathologyUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Department of PharmacologyUniversity of Colorado School of MedicineAuroraUSA
  3. 3.Department of Obstetrics and GynecologyUniversity of Colorado School of MedicineAuroraUSA

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