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Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay

Published online by Cambridge University Press:  08 March 2007

Serafim Kiriakidis ,
Oliver Högemeier ,
Susanne Starcke ,
Frank Dombrowski ,
Jens Claus Hahne ,
Michael Pepper ,
Hem Chandra Jha  and
Nicolas Wernert
Serafim Kiriakidis*
Affiliation:
Institute of Physiological Chemistry and
Oliver Högemeier
Affiliation:
Institute of Pathology, University of Bonn, Bonn, Germany
Susanne Starcke
Affiliation:
Institute of Physiological Chemistry and
Frank Dombrowski
Affiliation:
Institute of Pathology, University of Bonn, Bonn, Germany
Jens Claus Hahne
Affiliation:
Institute of Pathology, University of Bonn, Bonn, Germany
Michael Pepper
Affiliation:
Department of Morphology, University of Geneva Medical Center, Geneva, Switzerland
Hem Chandra Jha
Affiliation:
Institute of Physiological Chemistry and
Nicolas Wernert
Affiliation:
Institute of Pathology, University of Bonn, Bonn, Germany
*
*Corresponding author: Dr Serafim Kiriakidis, fax +44 20 8383 4499, email [email protected]
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Abstract

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Anti-angiogenic strategies are emerging as an important tool for the treatment of cancer and inflammatory diseases. In the present investigation we isolated several isoflavones from a tempeh (fermented soyabean) extract. The isolated isoflavones were identified as 5,7,4′-trihydroxyisoflavone (genistein), 7,4′-dihydroxyisoflavone (daidzein), 6,7,4′-trihydroxyisoflavone (factor 2), 7,8,4′-trihydroxyisoflavone (7,8,4′-TriOH) and 5,7,3′,4′-tetrahydroxyisoflavone (orobol). The effects on angiogenesis of these isoflavones were evaluated in the chicken chorioallantoic membrane assay; their capacity to inhibit vascular endothelial growth factor-induced endothelial cell proliferation and expression of the Ets 1 transcription factor, known to be implicated in the regulation of new blood vessel formation, were also investigated. We found that all isoflavones inhibited angiogenesis, albeit with different potencies. Compared with negative controls, which slightly inhibited in vivo angiogenesis by 6·30 %, genistein reduced angiogensis by 75·09 %, followed by orobol (67·96 %), factor 2 (56·77 %), daidzein (48·98 %) and 7,8,4′-TriOH (24·42 %). These compounds also inhibited endothelial cell proliferation, with orobol causing the greatest inhibition at lower concentrations. The isoflavones also inhibited Ets 1 expression, providing some insight into the molecular mechanisms of their action. Furthermore, the chemical structure of the different isoflavones suggests a structure–activity relationship. Our present findings suggest that the new isoflavones might be added to the list of low molecular mass therapeutic agents for the inhibition of angiogenesis.

Keywords

SoyabeanTempehIsoflavonesAngiogenesisEts 1
Type
Research Article
Information
British Journal of Nutrition , Volume 93 , Issue 3 , March 2005 , pp. 317 - 323
Copyright
Copyright © The Nutrition Society 2005

References

Akiyama, T, Ishida, J, Nakagawa, S, Ogawara, H, Watanabe, S, Itoh, N, Shibuya, M & Fukami, Y (1987) Genistein, a specific inhibitor of tyrosine specific protein kinases. J Biol Chem 262, 5592–5595.CrossRefGoogle ScholarPubMed
Auerbach, R, Lewis, R, Shinners, B, Kubai, L & Akhtar, N (2003) Angiogenesis assays: a critical overview. Clin Chem 49, 32–40.CrossRefGoogle ScholarPubMed
Belotti, D & Castronovo, V (1998) Tumor angiogenesis: basis for new prognostic factors and new anticancer therapies. In Clinical and Biological Basis for Lung Cancer Prevention, pp. 95–103 [Martinet, Y, editors]. Basel: Birkhaeuser.CrossRefGoogle Scholar
Brekken, RA, Overholser, JP, Stastny, VA, Waltenberger, J, Minna, JD & Thorpe, PE (2000) Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res 60, 5117–5124.Google ScholarPubMed
Brooks, PC, Montgomery, AM, Rosenfeld, M, Reisfeld, RA, Hu, T, Klier, G & Cheresh, DA (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157–1164.CrossRefGoogle ScholarPubMed
Carmeliet, P & Collen, D (2000) Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol 190, 387–405.3.0.CO;2-R>CrossRefGoogle ScholarPubMed
Carmeliet, P & Jain, RK (2000) Angiogenesis in cancer and other diseases. Nature 407, 249–257.CrossRefGoogle ScholarPubMed
Chen, CT, Lin, J & Li, Q (2000) Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin. Hum Gene Ther 11, 1983–1996.CrossRefGoogle ScholarPubMed
De Vries, C, Escobedo, JA, Ueno, H, Houck, K, Ferrara, N & Williams, LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989–991.CrossRefGoogle ScholarPubMed
Dionne, CA, Crumley, G, Bellot, F, Kaplow, JM, Searfoss, G, Ruta, M, Burgess, WH, Jaye, M & Scjlessinger, J (1990) Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J 9, 2685–2692.CrossRefGoogle ScholarPubMed
Drixler, TA, Rinkes, IH, Ritchie, ED, van Vroonhoven, TJ, Gebbink, MF & Voest, EE (2000) Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. Cancer Res 60, 1761–1765.Google ScholarPubMed
Feldman, AL, Restifo, NP, Alexander, HR, Bartlett, DL, Hwu, P, Seth, P & Libutti, SK (2000) Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. Cancer Res 60, 1503–1506.Google ScholarPubMed
Fisher, RJ, Koizumi, S, Kondoh, A, Marino, JM, Mavrothalassitis, G, Bhat, NK & Papas, TS (1992) Human Ets1 oncoprotein purification, isoforms, SH modification, and DNA sequence specific binding. J Biol Chem 267, 17957–17965.CrossRefGoogle ScholarPubMed
Fleischman, LF, Holtzclaw, L, Russell, JT, Mavrothalassitis, G & Fisher, RJ (1995) ets-1 in astrocytes: expression and transmitter-evoked phosphorylation. Mol Cell Biol 15, 925–993.CrossRefGoogle ScholarPubMed
Folkman, J (1995) Angiogenesis in cancer, vascular, rheumatoid, and other diseases. Nat Med 1, 27–31.CrossRefGoogle Scholar
Fotsis, T (1995) Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125, 790S–797S.Google ScholarPubMed
Fotsis, T, Pepper, MS, Aktas, E, Breit, S, Rasku, S, Adlercreutz, H, Wähälä, K, Montesano, R & Schweigerer, L (1997) Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res 57, 2916–2921.Google ScholarPubMed
György, P, Murata, K & Ikehata, H (1964) Antioxidants isolated from fermented soybeans (Tempe). Nature 203, 870–872.CrossRefGoogle Scholar
Huang, C, Papas, TS & Bhat, NK (1997) A variant form of Ets1 induces apoptosis in human colon cancer cells. Oncogene 15, 851–856.CrossRefGoogle ScholarPubMed
Ingber, D, Fujita, T, Kishimoto, S, Sudo, K, Kanamaru, T, Brem, H & Folkman, J (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348, 555–557.CrossRefGoogle ScholarPubMed
Iwasaka, C, Tanaka, K, Abe, M & Sato, Y (1996) Ets 1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. J Cell Physiol 169, 522–531.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
Jorcyk, CL, K, WD, Mavrothalassitis, GJ & Papas, TS (1991) The human Ets1 gene: genomic structure, promoter characterization and alternative splicing. Oncogene 6, 523–532.Google ScholarPubMed
Kerbel, RS (1997) A cancer therapy resistant to resistance. Nature 390, 335–336.CrossRefGoogle ScholarPubMed
Kilpatrick, LM, Kola, I & Salamonsen, LA (1999) Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells. Biol Reprod 61, 120–126.CrossRefGoogle ScholarPubMed
Klus, K & Barz, W (1995) Formation of polyhydroxylated isoflavones from the soybean seed isoflavones daidzein and glycitein by bacteria isolated from tempe. Arch Microbiol 164, 428–434.CrossRefGoogle ScholarPubMed
Li, R, Pei, H & Papas, T (1999) The p42 variant of ETS1 protein rescues defective Fas-induced apoptosis in colon carcinoma cells. Proc Natl Acad Sci USA 96, 3876–3881.CrossRefGoogle ScholarPubMed
Pepper, MS (2000) Angiogénèse et morphogenèse de l'arbre vasculaire: de la biologie cellulaire à la clinique (Angiogenesis and morphogenesis of the vascular tree: From cell biology to the clinic). Médecine/Science 16, 1378–1386.CrossRefGoogle Scholar
Pepper, MS (2001) Extracellular proteolysis and angiogenesis. Thromb Haemost 86, 346–355.Google ScholarPubMed
Pfeifer, A, Kessler, T, Silletti, S, Cheresh, DA & Verma, IM (2000) Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc Natl Acad Sci USA 97, 12227–12232.CrossRefGoogle ScholarPubMed
Sarkar, FH & Li, Y (2003) Soy isoflavones and cancer prevention. Cancer Invest 21, 744–757.CrossRefGoogle ScholarPubMed
Shiose, S, Sakamoto, T, Yoshikawa, H, Hata, Y, Kawano, Y, Ishibashi, T, Inomata, H, Takayama, K & Ueno, H (2000) Gene transfer of a soluble receptor of VEGF inhibits the growth of experimental eyelid malignant melanoma. Invest Ophthalmol Vis Sci 41, 2395–2403.Google ScholarPubMed
Takayama, K, Ueno, H, Nakanishi, Y, Sakamoto, T, Inoue, K, Shimizu, K, Oohashi, H & Hara, N (2000) Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ. Cancer Res 60, 2169–2177.Google ScholarPubMed
Vajkoczy, P, Thurnher, A, Hirth, KP, Schilling, L, Schmiedek, P, Ullrich, A & Menger, MD (2000) Measuring VEGF-Flk-1 activity and consequences of VEGF-Flk-1 targeting in vivo using intravital microscopy: clinical applications. Oncologist 5 Suppl. 1 16–19.CrossRefGoogle ScholarPubMed
Valter, M, Hugel, A, Huang, HJ, Cavenee, WK, Wiestler, OD, Pietsch, T & Wernert, N (1999) Expression of the Ets-1 transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis. Cancer Res 59, 5608–5614.Google ScholarPubMed
Vandenbunder, B, Pardanaud, L, Jaffredo, T, Mirabel, MA, Stéhelin, D (1989) Complementary patterns of expression of c- ets 1, c- myb and c- myc in the blood forming system of the chick embryo. Development 107, 265–274.CrossRefGoogle Scholar
Vitaliti, A, Wittmer, M, Steiner, R, Wyder, L, Neri, D & Klemenz, R (2000) Inhibition of tumor angiogenesis by a single-chain antibody directed against vascular endothelial growth factor. Cancer Res 60, 4311–4314.Google ScholarPubMed
Wernert, N (1997) The multiple roles of tumour stroma. Virch Arch 430, 433–443.CrossRefGoogle ScholarPubMed
Wernert, N, Justen, HP, Rothe, M, Behrens, P, Dreschers, S, Neuhaus, T, Florin, A, Sachinidis, A, Vetter, H & Ko, Y (2002) The Ets 1 transcription factor is upregulated during inflammatory angiogenesis in rheumatoid arthritis. J Mol Med 80, 258–266.CrossRefGoogle ScholarPubMed
Wernert, N, Raes, MB, Lasalle, P, Gosselin, B, Vandenbunder, B, Stéhelin, D (1992) The c- ets 1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in man. Am J Pathol 140, 119–127.Google Scholar
Wernert, N, Stanjek, A, Kiriakidis, S, Hügel, A, Jha, HC, Mazitschek, R & Giannis, A (1999) Inhibition of angiogenesis in vivo by ets-1 antisense oligonucleotides – inhibition of Ets-1 transcription factor expression by the antibiotic Fumagillin. Angew Chem Int Ed Engl 38, 3228–3231.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Yancopoulos, GD, Davies, S, Gale, NW, Rudge, JS, Wiegand, SJ & Holash, J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407, 242–247.CrossRefGoogle ScholarPubMed
Yasuda, M, Ohzeki, Y, Shimizu, S, Naito, S, Ohtsuru, A, Yamamoto, T & Kuroiwa, Y (1999) Stimulation of in vitro angiogenesis by hydrogen peroxide and the relation with ETS-1 in endothelial cells. Life Sci 64, 249–258.CrossRefGoogle ScholarPubMed