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Reduced isoflavone metabolites formed by the human gut microflora suppress growth but do not affect DNA integrity of human prostate cancer cells

Published online by Cambridge University Press:  19 February 2008

Marian Raschke ,
Kristiina Wähälä  and
Beatrice L. Pool-Zobel
Marian Raschke
Affiliation:
Institute for Nutritional Sciences, Department of Nutritional Toxicology, Friedrich-Schiller-University, Dornburger Strasse 25, 07743 Jena, Germany
Kristiina Wähälä
Affiliation:
Department of Organic Chemistry, University of Helsinki, A.I. Virtasen aukio 1, FIN-00014 Helsinki, Finland
Beatrice L. Pool-Zobel*
Affiliation:
Institute for Nutritional Sciences, Department of Nutritional Toxicology, Friedrich-Schiller-University, Dornburger Strasse 25, 07743 Jena, Germany
*
*Corresponding author: Professor Dr Beatrice L. Pool-Zobel, fax +49 3641 949672, email [email protected]
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Abstract

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Dietary isoflavones, such as genistein and daidzein, are metabolised by the human gut microflora. Case–control studies have disclosed a link between the formation of the daidzein metabolite equol and prostate cancer risk. We evaluated the effects of genistein, daidzein and five metabolites on two prostate cancer cell lines by determining DNA integrity and cell growth. LNCaP cells contain the T877A androgen receptor mutation whereas Los Angeles prostate cancer (LAPC)-4 cells express the wild-type receptor, both of which may affect responses to isoflavones. DNA integrity was determined using the comet assay. Cell growth was assessed by staining DNA with 4′,6′-diamidino-2-pheylindole hydrochloride. Endogenous steroid hormones, but not isoflavones, induced DNA strand breaks. Dihydrotestosterone stimulated the growth of both cell lines. 17β-Oestradiol increased the growth of LNCaP but not LAPC-4 cells, pointing to an involvement of the T877A androgen receptor. Isoflavones did not stimulate growth in either prostate cancer cell line. However, the growth of LNCaP and LAPC-4 cells was suppressed by genistein (inhibitory concentration 50% (IC50) 39·7μmo/, 37·2μmo/) and by equol (IC50 53·8μmo/, 35·1μmo/). O-desmethylangolensin inhibited the growth of LAPC-4 cells (IC50 45·2μmo/), but not of LNCaP cells. In conclusion, isoflavones do not damage DNA or promote growth of androgen-dependent prostate cancer cells. Several isoflavones, including the reduced daidzein metabolites equol and O-desmethylangolensin, suppress cancer cell growth. Taken together, these data suggest a contribution of gut-formed isoflavone metabolites to the beneficial effects of dietary isoflavones on prostate cancer risk.

Keywords

IsoflavonesProstate cancerCell growthDNA damage
Type
Research Article
Information
British Journal of Nutrition , Volume 96 , Issue 3 , September 2006 , pp. 426 - 434
Copyright
Copyright © The Nutrition Society 2006

References

Adlercreutz, H (2002) Phyto-oestrogens and cancer. Lancet Oncol 3, 364–373.CrossRefGoogle ScholarPubMed
Akaza, H, Miyanaga, N, Takashima, N, Naito, S, Hirao, Y, Tsukamoto, T & Mori, M (2002) Is daidzein non-metabolizer a high risk for prostate cancer? A case-controlled study of serum soybean isoflavone concentration. Jpn J Clin Oncol 32, 296–300.CrossRefGoogle ScholarPubMed
Akaza, H, Miyanaga, N, Takashima, N, et al. (2004) Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents. Jpn J Clin Oncol 34, 86–89.CrossRefGoogle ScholarPubMed
Arnold, JT, Le, H, McFann, KK & Blackman, MR (2005) Comparative effects of DHEA versus testosterone, dihydrotestosterone and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells. Am J Physiol 288, E573–E584.Google Scholar
Beck, V, Unterrieder, E, Krenn, L, Kubelka, W & Jungbauer, A (2003) Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol 84, 259–268.CrossRefGoogle ScholarPubMed
Bloedon, LT, Jeffcoat, AR, Lopaczynski, W, Schell, MJ, Black, TM, Dix, KJ, Thomas, BF, Albright, C, Busby, MG, Crowell, JA & Zeisel, SH (2002) Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women. Am J Clin Nutr 76, 1126–1137.CrossRefGoogle ScholarPubMed
Dagnelie, PC, Schuurman, AG, Goldbohm, RA & Van den Brandt, PA (2004) Diet, anthropometric measures and prostate cancer risk: a review of prospective cohort and intervention studies. BJU Int 93, 1139–1150.CrossRefGoogle Scholar
Di, Virgilio AL, Iwami, K, Watjen, W, Kahl, R & Degen, GH (2004) Genotoxicity of the isoflavones genistein, daidzein and equol in V79 cells. Toxicol Lett 151, 151–162.Google Scholar
Gomez, SL, Le, GM, Clarke, CA, Glaser, SL, France, AM & West, DW (2003) Cancer incidence patterns in Koreans in the US and in Kangwha, South Korea. Cancer Causes Control 14, 167–174.CrossRefGoogle ScholarPubMed
Hedlund, TE, Johannes, WU & Miller, GJ (2003) Soy isoflavonoid equol modulates the growth of benign and malignant prostatic epithelial cells in vitro. Prostate 54, 68–78.CrossRefGoogle ScholarPubMed
Hedlund, TE, Maroni, PD, Ferucci, PG, Dayton, R, Barnes, S, Jones, K, Moore, R, Ogden, LG, Wahala, K, Sackett, HM & Gray, KJ (2005) Long-term dietary habits affect soy isoflavone metabolism and accumulation in prostatic fluid in caucasian men. J Nutr 135, 1400–1406.CrossRefGoogle ScholarPubMed
Heinonen, S, Wahala, K & Adlercreutz, H (1999) Identification of isoflavone metabolites dihydrodaidzein, dihydrogenistein, 6′-OH-O-DMA, and cis-4-OH-equol in human urine by gas chromatography-mass spectroscopy using authentic reference compounds. Anal Biochem 274, 211–219.CrossRefGoogle Scholar
Hsing, AW, Tsao, L & Devesa, SS (2000) International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 85, 60–67.3.0.CO;2-B>CrossRefGoogle ScholarPubMed
Igawa, T, Lin, FF, Lee, MS, Karan, D, Batra, SK & Lin, MF (2002) Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 50, 222–235.CrossRefGoogle ScholarPubMed
Jemal, A, Thomas, A, Murray, T & Thun, M (2002) Cancer statistics, 2002. CA Cancer J Clin 52, 23–47.CrossRefGoogle ScholarPubMed
Klein, KA, Reiter, RE, Redula, J, et al. (1997) Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 3, 402–408.CrossRefGoogle ScholarPubMed
Kuiper, GG, Carlsson, B, Grandien, K, Enmark, E, Haggblad, J, Nilsson, S & Gustafsson, JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870.CrossRefGoogle ScholarPubMed
Kuiper, GG, Lemmen, JG, Carlsson, B, Corton, JC, Safe, SH, van der Saag, PT, van der, BB & Gustafsson, JA (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252–4263.CrossRefGoogle ScholarPubMed
Kulling, SE, Honig, DM & Metzler, M (2001) Oxidative metabolism of the soy isoflavones daidzein and genistein in humans in vitro and in vivo. J Agric Food Chem 49, 3024–3033.CrossRefGoogle ScholarPubMed
Kulling, SE & Metzler, M (1997) Induction of micronuclei, DNA strand breaks and HPRT mutations in cultured Chinese hamster V79 cells by the phytoestrogen coumoestrol. Food Chem Toxicol 35, 605–613.CrossRefGoogle ScholarPubMed
Lee, C, Sutkowski, DM, Sensibar, JA, Zelner, D, Kim, I, Amsel, I, Shaw, N, Prins, GS & Kozlowski, JM (1995) Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology 136, 796–803.CrossRefGoogle ScholarPubMed
Liggins, J, Bluck, LJ, Runswick, S, Atkinson, C, Coward, WA & Bingham, SA (2000) Daidzein and genistein contents of vegetables. Br J Nutr 84, 717–725.CrossRefGoogle ScholarPubMed
Maggiolini, M, Vivacqua, A, Carpino, A, Bonofiglio, D, Fasanella, G, Salerno, M, Picard, D & Ando, S (2002) The mutant androgen receptor T877A mediates the proliferative but not the cytotoxic dose-dependent effects of genistein and quercetin on human LNCaP prostate cancer cells. Mol Pharmacol 62, 1027–1035.CrossRefGoogle Scholar
Miltyk, W, Craciunescu, CN, Fischer, L, Jeffcoat, RA, Koch, MA, Lopaczynski, W, Mahoney, C, Jeffcoat, RA, Crowell, J, Paglieri, J & Zeisel, SH (2003) Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J Clin Nutr 77, 875–882.CrossRefGoogle ScholarPubMed
Mitchell, JH, Duthie, SJ & Collins, AR (2000) Effects of phytoestrogens on growth and DNA integrity in human prostate tumor cell lines: PC-3 and LNCaP. Nutr Cancer 38, 223–228.CrossRefGoogle ScholarPubMed
Morton, MS, Arisaka, O, Miyake, N, Morgan, LD & Evans, BA (2002) Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J Nutr 132, 3168–3171.CrossRefGoogle ScholarPubMed
Morton, MS, Chan, PS, Cheng, C, Blacklock, N, Matos-Ferreira, A, Branches-Monteiro, L, Correia, R, Lloyd, S & Griffiths, K (1997) Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. Prostate 32, 122–128.3.0.CO;2-O>CrossRefGoogle ScholarPubMed
Murata, M, Midorikawa, K, Koh, M, Umezawa, K & Kawanishi, S (2004) Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs. Biochemistry 43, 2569–2577.CrossRefGoogle ScholarPubMed
Onozawa, M, Fukuda, K, Ohtani, M, Akaza, H, Sugimura, T & Wakabayashi, K (1998) Effects of soybean isoflavones on cell growth and apoptosis of the human prostatic cancer cell line LNCaP. Jpn J Clin Oncol 28, 360–363.CrossRefGoogle ScholarPubMed
Ozasa, K, Nakao, M, Watanabe, Y, et al. (2004) Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Sci 95, 65–71.CrossRefGoogle Scholar
Pool-Zobel, BL, Adlercreutz, H, Glei, M, Liegibel, UM, Sittlingon, J, Rowland, I, Wahala, K & Rechkemmer, G (2000) Isoflavonoids and lignans have different potentials to modulate oxidative genetic damage in human colon cells. Carcinogenesis 21, 1247–1252.CrossRefGoogle ScholarPubMed
Quinn, M & Babb, P (2002) Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 90, 162–173.CrossRefGoogle ScholarPubMed
Record, IR, Jannes, M, Dreosti, IE & King, RA (1995) Induction of micronucleus formation in mouse splenocytes by the soy isoflavone genistein in vitro but not in vivo. Food Chem Toxicol 33, 919–922.CrossRefGoogle Scholar
Ren, MQ, Kuhn, G, Wegner, J & Chen, J (2001) Isoflavones, substances with multi-biological and clinical properties. Eur J Nutr 40, 135–146.CrossRefGoogle ScholarPubMed
Sack, JS, Kish, KF, Wang, C, et al. (2001) Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA 98, 4904–4909.CrossRefGoogle ScholarPubMed
Schaeferhenrich, A, Beyer-Sehlmeyer, G, Festag, G, et al. (2003) Human adenoma cells are highly susceptible to the genotoxic action of 4-hydroxy-2-nonenal. Mutat Res 526, 19–32.CrossRefGoogle Scholar
Schmitt, E, Metzler, M, Jonas, R, Dekant, W & Stopper, H (2003) Genotoxic activity of four metabolites of the soy isoflavone daidzein. Mutat Res 542, 43–48.CrossRefGoogle ScholarPubMed
Schuurmans, AL, Bolt, J, Veldscholte, J & Mulder, E (1991) Regulation of growth of LNCaP human prostate tumor cells by growth factors and steroid hormones. J Steroid Biochem Mol Biol 40, 193–197.CrossRefGoogle ScholarPubMed
Shimizu, H, Ross, RK, Bernstein, L, Yatani, R, Henderson, BE & Mack, TM (1991) Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 63, 963–966.CrossRefGoogle ScholarPubMed
Suzuki, H, Ueda, T, Ichikawa, T & Ito, H (2003) Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer 10, 209–216.CrossRefGoogle ScholarPubMed
Taplin, ME, Bubley, GJ, Ko, YJ, Small, EJ, Upton, M, Rajeshkumar, B & Balk, SP (1999) Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59, 2511–2515.Google ScholarPubMed
Valsta, LM, Kilkkinen, A, Mazur, W, Nurmi, T, Lampi, AM, Ovaskainen, ML, Korhonen, T, Adlercreutz, H & Pietinen, P (2003) Phyto-oestrogen database of foods and average intake in Finland. Br J Nutr 89, Suppl. 1, S31–S38.CrossRefGoogle ScholarPubMed
van Erp-Baart, MA, Brants, HA, Kiely, M, Mulligan, A, Turrini, A, Sermoneta, C, Kilkkinen, A & Valsta, LM (2003) Isoflavone intake in four different European countries: the VENUS approach. Br J Nutr 89, Suppl. 1, S25–S30.CrossRefGoogle ScholarPubMed
Watanabe, S, Yamaguchi, M, Sobue, T, Takahashi, T, Miura, T, Arai, Y, Mazur, W, Wahala, K & Adlercreutz, H (1998) Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako). J Nutr 128, 1710–1715.CrossRefGoogle ScholarPubMed
Wiseman, H, Casey, K, Bowey, EA, Duffy, R, Davies, M, Rowland, IR, Lloyd, AS, Murray, A, Thompson, R & Clarke, DB (2004) Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults. Am J Clin Nutr 80, 692–699.CrossRefGoogle ScholarPubMed