Summary
There have been many reports that high soya-based diets reduce the risk of certain types of cancer. This effect may be due to the presence of high levels of isoflavones derived from the soya bean, particularly genistein which has been shown to be a protein tyrosine kinase (PTK) inhibitor and have both oestrogenic and anti-oestrogenic properties. We have examined the effect of genistein and a number of novel synthetic analogues on both normal (IEC6, IEC18) and transformed (SW620, HT29) intestinal epithelial cell lines. Responses were compared to those elicited by oestradiol, the anti-oestrogen tamoxifen, and the tyrosine kinase inhibitor tyrphostin. Genistein and tamoxifen were potent inhibitors of cell proliferation. Of seven novel isoflavones tested, none were more potent inhibitors than genistein, and all displayed similar relative activities across the different cell lines. In addition to inhibiting cell proliferation, cell death via apoptosis was observed when the cells were exposed to the isoflavones and all but one exhibited PTK inhibitory activity. These data suggest that by reducing proliferation and inducing apoptosis, possibly due in part to PTK inhibition, isoflavones may have a role in protecting normal intestinal epithelium from tumour development (reducing the risk) and may reduce colonic tumour growth.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Adlercreutz, H. (1990). Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest 50: 3–23.
Adlercreutz, H., Markkanen, H. & Watanabe, S. (1993). Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342: 1209–1210.
Akiyama, T., Ishida, J., Nakagawa, S., Ogawara, H., Watanabe, S., Itoh, N., Masabumi, S. & Fukami, Y. (1987). Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 25: 5592–5595.
Armstrong, B. & Doll, R. (1975). Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Intl J Cancer 15: 617–631.
Barnes, S., Peterson, G. & Coward, B. S. (1995). Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer. J Cell Biochem 22: 181–187.
Booth, C. et al (1995). The isolation and culture of adult mouse colonic epithelium. Epithelial Cell Biol 4: 76–86.
Boyle, P., Zaridze, D. G. & Smans, M. (1985). Descriptive epidemiology of colorectal cancer. Intl J Cancer 36: 9–18.
Casnellie, J., Harrison, M., Pike, L., Hellstrom, K. & Krebs, E. (1982). Phosphorylation of synthetic peptides by a tyrosine protein kinase from the particulate fraction of a lymphoma cell line. Proc Natl Acad Sci USA 79: 282–286.
Constantinou, A., Kiguchi, K. & 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.
Fotsis, T., Pepper, M., Aldercreutz, H., Fleischmann, G., Hase, T., Montesano, R. & Schweigerer, L. (1993). Genistein, a dietary derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 90: 2690–2694.
Hoff, M. B., Chang, W. W. L. & Mak, K. M. (1981). Effect of estrogen on cell proliferation in colonic mucosa of the mouse. Virchows Arch 35: 263–273.
Ingram, D., Sanders, K., Kolybaba, M. & Lopez, D. (1997). Case-control study of phyto-oestrogens and breast cancer. Lancet 350: 990–994.
Kampman, E., Potter, J. D., Slattery, M. L., Caan, B. J. & Edwards, S. (1997). Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control 8: 146–158.
Kuo, S. (1996). Antiproliferative potency of structurally distinct isoflavanoids on human colon cancer cells. Cancer Lett 110: 41–48.
Lamartiniere, C. A., Moore, J., Holland, M. & Barnes, S. (1995). Neonatal genistein chemoprevents mammary cancer. Proc Soc Exp Biol Med 208: 120–123.
Lee, H. P., Gourley, L., Duffy, S. W., Esteve, J., Lee, J. & Day, N. E. (1995). Dietary effects on breast-cancer risk in Singapore. Lancet 337: 1197–1200.
Martin, P. M., Horwitz, K. B., Ryan, D. S. & McGuire, W. L. (1978). Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103: 1860–1867.
McMichael-Phillips, D. F., Harding, C., Morton, M., Howell, A., Potten, C. S. & Bundred, N. J. (1996). The effects of soy supplementation on epithelial proliferation in the normal human breast. Breast Cancer Res Treat 41: 263
Messina, M. J., Persky, V., Setchell, K. D. R. & Barnes, S. (1994). Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 21: 113–131.
Negi, R. K. S., Rajagopalan, T. R. & Batra, V. (1985). Flavanoidal constituents of Lupinus hirsutus. Indian J Chem 24B: 221
Ogawara, H., Akiyama, T., Watanabe, S., Ito, N., Kobori, M. & Seoda, Y. (1989). Inhibition of tyrosine protein kinase activity by synthetic isoflavones and flavones. J Antibiot Tokyo 42: 340–343.
Okura, A., Arakawa, H., Oka, H., Yoshinari, T. & Monden, Y. (1988). Effect of genistein on topoisomerase activity and on the growth of [val12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Comm 157: 183–189.
Pagliacci, M. C., Smachia, M., Migliorati, F., Grignani, F., Riccardi, C. & Nicoletti, I. (1994). Growth-inhibitory effects of the natural phytoestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer 30A: 1675–1682.
Peterli, F., Stumpf, R., Schweizer, M., Sequin, U., Mett, H. & Praxler, P. (1992). Nitrostyrene derivatives of adenosine 5′-glutarates as selective inhibitors of the epidermal growth factor receptor protein tyrosine kinase. Helv Chim Acta 75: 696–706.
Potten, C. S., Booth, C., Chadwick, C. A. & Evans, G. S. (1993). A potent stimulator of small intestinal cell proliferation extracted by simple diffusion from intact irradiated intestine: in vitro studies. Growth Factors 10: 53–61.
Potter, J. D., Bostick, R. M., Grandits, G. A., Fosdick, L., Elmer, P., Wood, J., Grambasch, P. & Louis, T. A. (1996). Hormone replacement therapy is associated with lower risk of adenomatous polyps of the large bowel: the Minnesota Cancer Prevention Research Unit Case-Control Study. Cancer Epidemiol Bio Prev 5: 779–784.
Powis, G. & Kozikowski, A. (1991). Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. Clin Biochem 24: 385–397.
Quaroni, A. & May, R. J. (1980). Establishment and characterisation of intestinal epithelial cell cultures. Methods Cell Biol 21B: 403–427.
Severson, R. K., Nomura, A. M. Y., Grove, J. S. & Stemmermann, G. N. (1989). A prospective study of demographics, diet and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 49: 1857–1860.
Singh, S., Paraskeva, C., Gallimore, P. H., Sheppard, M. C. & Langman, M. J. (1994). Differential growth response to oestrogen of premalignant and malignant colonic cell lines. Anticancer Res 14: 1037–1041.
Thomas, M. L. T., Xu, X., Norfleet, A. M. & Watson, C. S. (1993). The presence of functional estrogen receptors in intestinal epithelial cells. Endocrinology 132: 426–430.
Toi, M., Mukaida, H., Wada, T., Hirabayashi, N., Toge, T., Hori, T. & Umezawa, K. (1990). Antineoplastic effect of erbstatin on human mammary and esophageal tumors in athymic nude mice. Eur J Cancer 26: 722–724.
Troll, W., Wiesner, R., Shellabarger, C. J., Holtzman, S. & Stone, J. P. (1980). Soybean diet lowers breast tumor incidence in irradiated rats. Carcinogenesis 1: 469–472.
Wang, B. H., Ternai, B. & Poly, G. (1997). Specific inhibition of cyclic AMP-dependent protein kinase by warangalone and robustic acid. Phytochemistry 44: 787–796.
Wang, H. & Murphy, P. A. (1994). Isoflavone content in commercial soybean foods. J Agric Food Chem 42: 1666–1673.
Wei, H., Wei, L., Frenkel, Bowen, R. & Barnes, S. (1993). Inhibition of tumour promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein. Nutr Cancer 20: 1–12.
Welshons, W. V., Murphy, C. S., Koch, R., Calaf, G. & Jordan, V. C. (1987). Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol. Breast Cancer Res Treat 10: 169–175.
Willett, W. C. (1995). Diet, nutrition and avoidable cancer. Environmental Health Perspectives 103: 165–170.
Xu, X. & Thomas, M. L. (1994). Estrogen receptor mediated direct stimulation of colon cell growth in vitro. Mol Cell Endocrinol 105: 197–201.
Xu, X. et al (1994). Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J Nutr 124: 825–832.
Yanagihara, K., Ito, A., Toge, T. & Numoto, M. (1993). Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 53: 5815–5821.
Yoshida, M., Sakai, T., Hosokawa, N., Marui, N., Matsumoto, K., Fujioka, A., Nishino, H. & Aoike, A. (1990). The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett 260: 10–13.
Zava, D. T. & Duwe, G. (1997). Estrogenic and antiproliferative properties of genistein and other isoflavonoids in human breast cancer cells in vitro. Nutr Cancer 27: 31–40.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Booth, C., Hargreaves, D., Hadfield, J. et al. Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro. Br J Cancer 80, 1550–1557 (1999). https://doi.org/10.1038/sj.bjc.6690559
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690559
Keywords
This article is cited by
-
Synthesis of 3-heteroarylchromones via a photochemical reaction
Molecular Diversity (2016)
-
Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis
European Journal of Nutrition (2016)
-
Effects of Storage Conditions on the Stability of Isoflavone Isomers in Lactic Fermented Soymilk Powder
Food and Bioprocess Technology (2013)
-
Bioconversion of isoflavones during the fermentation of Samso-Eum with Lactobacillus strains
Biotechnology and Bioprocess Engineering (2012)
-
Effect of genistein on cholesterol metabolism-related genes in a colon cancer cell line
Genes & Nutrition (2008)