Abstract
Compounds based on a flavonoid (di-phenolic) ring structure are emerging as a potentially important new class of pharmaceutical compounds with a broad range of biological activities, most prominent of which are their potential role as anticancer agents. These compounds exert a wide range of upregulating and downregulating effects on signal transduction processes within cells in both plants and animals. The observation that human communities, which consume large quantities of these compounds (legume-based vegetarian diets), have a lower incidence of many degenerative diseases and some cancers has led to the speculation that these compounds, or synthetic analogs, may be of therapeutic value. This article reviews the evidence supporting this hypothesis and provides some examples of attempts to develop new therapeutics based on dietary isoflavones or novel isoflavonoid structures in maintaining prostate health and in cancer treatment and management. One of these compounds, phenoxodiol, is now in human clinical trials and has shown promise in patients with recurrent ovarian cancer where the cancer is refractory or resistant to standard chemotherapy, and in patients with hormone-refractory prostate cancer.
Similar content being viewed by others
References
Adlercreutz, H., Fotsis, T., Heikkinen, et al. (1982) Excretion of the lignans enterolactone and enterodiol and of equol in omnivorous and vegetarian postmenopausal women and in women with breast cancer. Lancet 2, 1295–1299.
Ekman, P. (1989) BPH epidemiology and risk factors. Prostate Suppl. 2, 23–31.
Dhom, G. (1991) Epidemiology of hormone-depending tumors. In: Endocrine Dependent Tumors (Voigt, K. D. and Knabbe, C., eds.), Raven Press, New York, pp. 1–42.
Mills, P. K., Beeson, W. L., Phillips, R. L., and Fraser, G. E. (1989) Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer 64, 598–604.
Dunn, J. E. (1975) Cancer epidemiology in populations of the United States—with emphasis on Hawaii and California—and Japan. Cancer Res. 35, 3240–3245.
Kolonel, L. N., Hankin, J. H., and Nomura, A. M. Y. (1986) Multiethnic studies of diet, nutrition and cancer in Hawaii. In: Nutrition and Cancer (Hayashi, Y., ed.), Japanese Science Society Press, Tokyo, pp. 29–40.
Jarred, R. A., Keikha, M., Dowling, C., et al. (2002) Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol. Biomarkers Prev. 11, 1689–1696.
Setchell, K. D. R. and Adlercreutz, H. (1988) Mammalian lignans and phyto-oestrogens. Recent studies on their formation, metabolism and biological role in health and disease. In: Role of the Gut Flora in Toxicity and Cancer (Rowland, I. R., ed.), Academic Press Limited, San Diego, pp. 315–345.
Kelly, G. E., Nelson, C., Waring, M. A., Joannou, G. E., and Reeder, A. Y. (1993) Metabolites of dietary (soya) isoflavones in human urine. Clin. Chim. Acta 223, 9–22.
Miksicek, R. J. (1994) Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor. J. Steroid Biochem. Mol. Biol. 49, 153–160.
Collins, B. M., McLachlan, J. A., and Arnold, S. F. (1997) The estrogenic and antiestrogenic activities of phytochemicals with human estrogen receptor expressed in yeast. Steroids 62, 365–372.
Miksicek, R. J. (1993) Commonly occurring plant flavonoids have estrogenic activity. Mol. Pharmacol. 44, 37–43.
Cato, A. C., Miksicek, R., Schutz, G., Arnemann, J., and Beato, M. (1986) The hormone regulatory element of mouse mammary tumour virus mediates progesterone induction. EMBO J. 5, 2237–2240.
Campbell, D. R. and Kurzer, M. S. (1993) Flavonoid inhibition of aromatase enzyme activity in human preadipocytes. J. Steroid Biochem. Mol. Biol. 46, 381–388.
Morton, M. S., Griffiths, K., and Blacklock, N. (1996) The preventive role of diet in prostatic disease. Brit. J. Urol. 77, 481–493.
Evans, B. A., Griffiths, K., and Morton, M. S. (1995) Inhibition of 5 alpha-reductase in genital skin fibro-blasts and prostate tissue by dietary lignans and isoflavonoids. J. Endocrinol. 147, 295–302.
Bruchovsky, N. and Wilson, J. D. (1968) The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. J. Biol. Chem. 243, 2012–2021.
Anderson, K. M. and Liao, S. (1968) Selective retention of dihydrotestosterone by prostatic nuclei. Nature (Lond.) 219, 277–279.
Keung, W. M. (1995) Dietary estrogenic isoflavones are potent inhibitors of beta-hydroxysteroid dehydrogenase of P. testosteronii. Biochem. Biophys. Res. Commun. 215, 1137–1144.
Wong, C. K. and Keung, W. M. (1997) Daidzein sulfoconjugates are potent inhibitors of sterol sulfatase (EC 3.1.6.2). Biochem. Biophys. Res. Commun. 233, 579–583.
Sun, X. Y., Plouzek, C. A., Henry, J. P., Wang, T. T., and Phang, J. M. (1998) Increased UDP-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin A in prostate cancer cells. Cancer Res. 58, 2379–2384.
Akiyama, T., Ishida, J., Nakagawa, S., et al. (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 262, 5592–5595.
Suolinna, E. M., Lang, D. R., and Racker, E. (1974) Quercetin, an artificial regulator of the high aerobic glycolysis of tumor cells. J. Natl. Cancer Inst. 53, 1515–1519.
Shoshan, V. and MacLennan, D. H. (1981) Quercetin interaction with the (Ca2+ + Mg2+)-ATPase of sarcoplasmic reticulum. J. Biol. Chem. 256, 887–892.
Ono, K., Nakane, H., Fukushima, M., Chermann, J. C., and Barre-Sinoussi, F. (1990) Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases [published erratum appears in Eur. J. Biochem. 1991;199:769]. Eur. J. Biochem. 190, 469–476.
Glossmann, H., Presek, P., and Eigenbrodt, E. (1981) Quercetin inhibits tyrosine phosphorylation by the cyclic nucleotide-independent, transforming protein kinase, pp60src. Naunyn Schmiedebergs Arch. Pharmacol. 317, 100–102.
Matter, W. F., Brown, R. F., and Vlahos, C. J. (1992) The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs. Biochem. Biophys. Res. Commun. 186, 624–631.
Prajda, N., Singhal, R. L., Yeh, Y. A., Olah, E., Look, K. Y., and Weber, G. (1995) Linkage of reduction in 1-phosphatidylinositol 4-kinase activity and inositol 1,4,5-trisphosphate concentration in human ovarian carcinoma cells treated with quercetin. Life Sci. 56, 1587–1593.
Rizzo, M. T. and Weber, G. (1994) 1-Phosphatidylinositol 4-kinase: an enzyme linked with proliferation and malignancy. Cancer Res. 54, 2611–2614.
Yoshida, M., Yamamoto, M., and Nikaido, T. (1992) Quercetin arrests human leukemic T-cells in late G1 phase of the cell cycle. Cancer Res. 52, 6676–6681.
Scambia, G., Ranelletti, F. O., Panici, P. B., et al. (1990) Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells. Br. J. Cancer 62, 942–946.
Wei, Y. Q., Zhao, X., Kariya, Y., Fukata, H., Teshigawara, K., and Uchida, A. (1994) Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res. 54, 4952–4957.
Avila, M. A., Velasco, J. A., Cansado, J., and Notario, V. (1994) Quercetin mediates the down-regulation of mutant p53 in the human breast cancer cell line MDA-MB468. Cancer Res. 54, 2424–2428.
Constantinou, A. and Huberman, E. (1995) Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc. Soc. Exp. Biol. Med. 208, 109–115.
Traganos, F., Ardelt, B., Halko, N., Bruno, S., and Darzynkiewicz, Z. (1992) Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res. 52, 6200–6208.
Constantinou, A., Kiguchi, K., and Huberman, E. (1990) Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Res. 50, 2618–2624.
Peterson, G. and Barnes, S. (1991) Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem. Biophys. Res. Commun. 179, 661–667.
Peterson, G. and Barnes, S. (1996) Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ. 7, 1345–1351.
Monti, E. and Sinha, B. K. (1994) Antiproliferative effect of genistein and adriamycin against estrogen-dependent and -independent human breast carcinoma cell lines. Anticancer Res. 14, 1221–1226.
Pagliacci, M. C., Smacchia, M., Migliorati, G., Grignani, F., Riccardi, C., and Nicoletti, I. (1994) Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur. J. Cancer 30A, 1675–1682.
Matsukawa, Y., Marui, N., Sakai, T., et al. (1993) Genistein arrests cell cycle progression at G2-M. Cancer Res. 53, 1328–1331.
Yanagihara, K., Ito, A., Toge, T., and Numoto, M. (1993) Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 53, 5815–5821.
Peterson, G. and Barnes, S. (1993) Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 22, 335–345.
Schweigerer, L., Christeleit, K., Fleischmann, G., et al. (1992) Identification in human urine of a natural growth inhibitor for cells derived from solid paediatric tumours. Eur. J. Clin. Invest. 22, 260–264.
Akiyama, T. and Ogawara, H. (1991) Use and specificity of genistein as inhibitor of protein-tyrosine kinases. Methods Enzymol. 201, 362–370.
Constantinou, A., Mehta, R., Runyan, C., Rao, K., Vaughan, A., and Moon, R. (1995) Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J. Natural Products 58, 217–225.
Watanabe, T., Kondo, K., and Oishi, M. (1991) Induction of in vitro differentiation of mouse erythroleukemia cells by genistein, an inhibitor of tyrosine protein kinases. Cancer Res. 51, 764–768.
Uckun, F. M., Evans, W. E., Forsyth, C. J., et al. (1995) Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science 267, 886–891.
Fotsis, T., Pepper, M., Adlercreutz, H., Hase, T., Montesano, R., and Schweigerer, L. (1995) Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J. Nutr. 125, 790S-797S.
Bergan, R., Kyle, E., Nguyen, P., Trepel, J., Ingui, C., and Neckers, L. (1996) Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin. Clin. Exp. Metastasis 14, 389–398.
Carlson, B. A., Dubay, M. M., Sausville, E. A., Brizuela, L., and Worland, P. J. (1996) Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 56, 2973–2978.
Shapiro, G. I., Koestner, D. A., Matranga, C. B., and Rollins, B. J. (1999) Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin. Cancer Res. 5, 2925–2938.
Drees, M., Dengler, W. A., Roth, T., et al. (1997) Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin. Cancer Res. 3, 273–279.
Axelson, M., Kirk, D. N., Farrant, R. D., Cooley, G., Lawson, A. M., and Setchell, K. D. (1982) The identification of the weak oestrogen equol [7-hydroxy-3-(4′-hydroxyphenyl)chroman] in human urine. Biochem. J. 201, 353–357.
Bannwart, C., Adlercreutz, H., Wahala, K., et al. (1988) Identification of the phyto-oestrogen 3′,7-dihydroxyisoflavan, an isomer of equol, in human urine and cow’s milk. Biomed. Environ. Mass Spectrom. 17, 1–6.
Joannou, G. E., Kelly, G. E., Reeder, A. Y., Waring, M., and Nelson, C. (1995) A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids. J. Steroid Biochem. Mol. Biol. 54, 167–184.
Bannwart, C., Fotsis, T., Heikkinen, R., and Adlercreutz, H. (1984) Identification of the isoflavonic phytoestrogen daidzein in human urine. Clin. Chim. Acta 136, 165–172.
Kok, J. W., Veldman, R. J., Klappe, K., Koning, H., Filipeanu, C. M., and Muller, M. (2000) Differential expression of sphingolipids in MRP1 overexpressing HT29 cells. Int. J. Cancer 87, 172–178.
Makela, S., Davis, V. L., Tally, W. C., et al. (1994) Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environ. Health Perspect. 102, 572–578.
Wang, C. and Kurzer, M. S. (1997) Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr. Cancer 28, 236–247.
Setchell, K. D., Borriello, S. P., Hulme, P., Kirk, D. N., and Axelson, M. (1984) Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am. J. Clin. Nutr. 40, 569–578.
Ingram, D., Sander, K., Kolybaba, M., and Lopez, D. (1998) Case-control study of phyto-oestrogens and breast cancer. Lancet 350, 990–994.
Adlercreutz, H., Goldin, B. R., Gorbach, S. L., et al. (1995) Soybean phytoestrogen intake and cancer risk. J. Nutr. 125, 757S-770S.
Pedersen, G., Brynskov, J., and Saermark, T. (2002) Phenol toxicity and conjugation in human colonic epithelial cells. Scand. J. Gastroenterol. 37, 74–79.
Aguero, M., Facchinetti, M. M., Sheleg, Z., and Senderowicz, A. M. (2005) Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1. Cancer Res. 65, 3364–3373.
Kamsteeg, M., Rutherford, T., Sapi, E., et al. (2003) Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22, 2611–2620.
Hengartner, M. O. (2000) The biochemistry of apoptosis. Nature (Lond.) 407, 770–776.
Deveraux, Q. L., Leo, E., Stennicke, H. R., Welsh, K., Salvesen, G. S., and Reed, J. C. (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 18, 5242–5251.
Cardone, M. H., Roy, N., Stennicke, H. R., et al. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318–1321.
Mabuchi, S., Ohmichi, M., Kimura, A., et al. (2002) Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J. Biol. Chem. 277, 33,490–33,500.
Igarashi, J., Bernier, S. G., and Michel, T. (2001) Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase. differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells. J. Biol. Chem. 276, 12420–12426.
Pettus, B. J., Chalfant, C. E., and Hannun, Y. A. (2002) Ceramide in apoptosis: an overview and current perspectives. Biochim. Biophys. Acta 1585, 114–125.
Geilen, C. C., Wieder, T., and Orfanos, C. E. (1997) Ceramide signalling: regulatory role in cell proliferation, differentiation and apoptosis in human epidermis. Arch. Dermatol. Res. 289, 559–566.
Senchenkov, A., Litvak, D. A., and Cabot, M. C. (2001) Targeting ceramide metabolism—a strategy for overcoming drug resistance. J. Natl. Cancer Inst. 93, 347–357.
Olivera, A., Kohama, T., Edsall, L., et al. (1999) Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J. Cell Biol. 147, 545–558.
Olivera, A. and Spiegel, S. (1993) Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature (Lond.) 365, 557–560.
Cuvillier, O. (2002) Sphingosine in apoptosis signaling. Biochim. Biophys. Acta 1585, 153–162.
Nava, V. E., Cuvillier, O., Edsall, L. C., et al. (2000) Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res. 60, 4468–4474.
Xia, P., Gamble, J. R., Wang, L., et al. (2000) An oncogenic role of sphingosine kinase. Curr. Biol. 10, 1527–1530.
French, K. J., Schrecengost, R. S., Lee, B. D., et al. (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 63, 5962–5969.
Bektas, M., Jolly, P. S., Muller, C., Eberle, J., Spiegel, S., and Geilen, C. C. (2005) Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene 24, 178–187.
Gamble, J. R., Xia, P., Hahn, C. N., et al. (2005) Phenoxodiol, a derivative of plant flavonoids, shows potent anti-tumour and anti-angiogenic properties. Int. J. Cancer, in preparation.
Bos, J. L. (1989) ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brown, D.M., Kelly, G.E. & Husband, A.J. Flavonoid compounds in maintenance of prostate health and prevention and treatment of cancer. Mol Biotechnol 30, 253–270 (2005). https://doi.org/10.1385/MB:30:3:253
Issue Date:
DOI: https://doi.org/10.1385/MB:30:3:253