Planta Med 2006; 72(6): 488-493
DOI: 10.1055/s-2005-916261
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

Estrogenic Activity of Isoflavonoids from Onobrychis ebenoides

Maria Halabalaki1 , Xanthippi Alexi2 , 3 , Nektarios Aligiannis1 , George Lambrinidis4 , Harris Pratsinis5 , Ida Florentin2 , Sofia Mitakou1 , Emmanuel Mikros4 , Alexios-Leandros Skaltsounis1 , Michael N. Alexis2
  • 1Division of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Athens, Greece
  • 2Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece
  • 3Present address: Cancer Research UK Institute for Cancer Studies, The University of Birmingham, Birmingham, UK
  • 4Division of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Athens, Greece
  • 5Institute of Biology, NCSR ”Demokritos”, Athens, Greece
Further Information

Publication History

Received: May 18, 2005

Accepted: November 22, 2005

Publication Date:
17 February 2006 (online)

Abstract

Fractionation of the neutral extract of Onobrychis ebenoides (Leguminosae) yielded a new isoflavone, named ebenosin (1), in addition to the known ones, afrormosin (2), formononetin (3) and daidzein (4). Although the relative binding affinities of 1 - 4 for estrogen receptor α (ERα) were nearly comparable and matched those of 1 - 3 for ERβ, that of 4 for the latter receptor was significantly higher than any of the other. Compounds 1 - 4 induced cell proliferation and gene expression in breast and endometrial cancer cells in an ER-dependent manner. Nonetheless, the rank order of induction potencies (4 > 321) matched better that of affinities for ERβ (4 > 321) rather than ERα (4321). While the antiestrogen ICI 182,780 could inhibit the induction of proliferation of ER-positive breast cancer cells by 1 - 4, it could not prevent 1 from exhibiting significant ER-independent cytotoxicity at 10 μM. By contrast, 1 was much less cytotoxic and only weakly estrogenic for ER-positive endometrial adenocarcinoma cells. In conclusion, our data suggest that the C-8 isoprenyl substituent of 1 renders it cytotoxic and/or estrogenic in a cell-dependent manner.

Abbreviations

AlkP:Alkaline Phosphatase

DCC-FBS:Dextran Coated Charcoal-treated Fetal Bovine Serum

EGF:Epidermal Growth Factor

ER:Estrogen Receptor

ERE:Estrogen Responsive Element

HRT:Hormone Replacement Therapy

RBA:Relative Binding Affinity

References

  • 1 Basly J P, Lavier M C. Dietary phytoestrogens: potential selective estrogen enzyme modulators?.  Planta Med. 2005;  71 287-94
  • 2 Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T. et al . Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.  Endocrinology. 1998;  139 4252-63
  • 3 Cos P, De Bruyne T, Apers S, Vanden Berghe D, Pieters L, Vlietinck A J. Phytoestrogens: recent developments.  Planta Med. 2003;  69 589-99
  • 4 Beck V, Rohr U, Jungbauer A. Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy?.  J Steroid Biochem Mol Biol. 2005;  94 499-518
  • 5 Baber R J, Templeman C, Morton T, Kelly G E, West L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women.  Climacteric. 1999;  2 85-92.
  • 6 Halabalaki M, Aligiannis N, Papoutsi Z, Mitakou S, Moutsatsou P, Sekeris C. et al . Three new arylobenzofurans from Onobrychis ebenoides and evaluation of their binding affinity for the estrogen receptor.  J Nat Prod. 2000;  63 1672-4
  • 7 Papoutsi Z, Kassi E, Papaevangeliou D, Pratsinis H, Zoumpourlis V, Halabalaki M. et al . Plant 2-arylobenzofurans demonstrate a selective estrogen receptor modulator profile.  Steroids. 2004;  69 727-34.
  • 8 Lu Y, Sun Y, Foo L Y, McNabb W C, Molan A L. Phenolic glycosides of forage legume Onobrychis viciifolia .  Phytochemistry. 2000;  55 67-75.
  • 9 Jayaprakasam B, Damu A G, Rao K V, Gunasekar D, Blond A, Bodo B. 7-O-Methyltetrahydroochnaflavone, a new biflavanone from Ochna beddomei .  J Nat Prod. 2000;  63 507-8
  • 10 Whalley J L, Bond T J, Botting N P. Synthesis of 13C labelled daidzein and formononetin.  Bioorg Med Chem Lett. 1998;  8 2569-72
  • 11 Fokialakis N, Lambrinidis G, Mitsiou D J, Aligiannis N, Mitakou S, Skaltsounis A L. et al . A new class of phytoestrogens; evaluation of the estrogenic activity of deoxybenzoins.  Chem Biol. 2004;  11 397-406
  • 12 Bhat K P, Pezzuto J M. Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells.  Cancer Res. 2001;  61 6137-44
  • 13 Kinjo J K, Furusawa J I, Baba J, Takeshita T, Yamasaki M, Nohara T. Studies on the constituents of Pueraria lobata. III. Isoflavonoids and related compounds in the roots and the voluble stems.  Chem Pharm Bull. 1987;  35 4846-50
  • 14 Yin S, Fan C Q, Wang Y, Dong L, Yue J M. Antibacterial prenylflavone derivatives from Psoralea corylifolia and their structure-activity relationship study.  Bioorg Med Chem. 2004;  12 4387-92
  • 15 De Cremoux P, Tran-Perennou C, Brockdorff B L, Boudou E, Brunner N, Magdelenat H. et al . Validation of real-time RT-PCR for analysis of human breast cancer cell lines resistant or sensitive to treatment with antiestrogens.  Endocr Relat Cancer. 2003;  10 409-18
  • 16 Lazennec G, Alcorn J L, Katzenellenbogen B S. Adenovirus-mediated delivery of a dominant negative estrogen receptor gene abrogates estrogen-stimulated gene expression and breast cancer cell proliferation.  Mol Endocrinol. 1999;  13 969-80
  • 17 Jang E R, Lim S J, Lee E S, Jeong G, Kim T Y, Bang Y J. et al . The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor alpha-negative breast cancer cells to tamoxifen.  Oncogene. 2004;  23 1724-36
  • 18 Paine T M, Soule H D, Pauley R J, Dawson P J. Characterization of epithelial phenotypes in mortal and immortal human breast cells.  Int J Cancer. 1992;  50 463-73
  • 19 Pettersson K, Delaunay F, Gustafsson J A. Estrogen receptor beta acts as a dominant regulator of estrogen signaling.  Oncogene. 2000;  19 4970-8
  • 20 Pike A C, Brzozowski A M, Hubbard R E, Bonn T, Thorsell A G, Engstrom O. et al . Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist.  EMBO J. 1999;  18 4608-18
  • 21 Ruh M F, Taylor J A, Howlett A C, Welshons W V. Failure of cannabinoid compounds to stimulate estrogen receptors.  Biochem Pharmacol. 1997;  53 35-41
  • 22 An J, Tzagarakis-Foster C, Scharschmidt T C, Lomri N, Leitman D C. Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens.  J Biol Chem. 2001;  276 17 808-14
  • 23 Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz J M, Moras D. Crystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonism.  J Biol Chem. 2001;  276 15 059-65
  • 24 Kitaoka M, Kadokawa H, Sugano M, Ichikawa K, Taki M, Takaishi S. et al . Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship.  Planta Med. 1998;  64 511-5
  • 25 Zierau O, Gester S, Schwab P, Metz P, Kolba S, Wulf M. et al . Estrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin.  Planta Med. 2002;  68 449-51

Dr. Michael N. Alexis

Institute of Biological Research and Biotechnology

National Hellenic Research Foundation

11635 Athens

Greece

Phone: +30-210-7273741

Fax: +30-210-7273677

Email: mnalexis@eie.gr