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British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Jul;80(10):1550–1557. doi: 10.1038/sj.bjc.6690559

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro

C Booth 1, D F Hargreaves 1, J A Hadfield 2, A T McGown 2, C S Potten 1
PMCID: PMC2363089  PMID: 10408396

Abstract

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. © 1999 Cancer Research Campaign

Keywords: genistein, isoflavones, epithelial cell, intestine, apoptosis

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Selected References

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  1. Adlercreutz H., Markkanen H., Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993 Nov 13;342(8881):1209–1210. doi: 10.1016/0140-6736(93)92188-y. [DOI] [PubMed] [Google Scholar]
  2. Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest Suppl. 1990;201:3–23. [PubMed] [Google Scholar]
  3. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987 Apr 25;262(12):5592–5595. [PubMed] [Google Scholar]
  4. Armstrong B., Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975 Apr 15;15(4):617–631. doi: 10.1002/ijc.2910150411. [DOI] [PubMed] [Google Scholar]
  5. Barnes S., Peterson T. G., Coward L. Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer. J Cell Biochem Suppl. 1995;22:181–187. doi: 10.1002/jcb.240590823. [DOI] [PubMed] [Google Scholar]
  6. Booth C., Patel S., Bennion G. R., Potten C. S. The isolation and culture of adult mouse colonic epithelium. Epithelial Cell Biol. 1995;4(2):76–86. [PubMed] [Google Scholar]
  7. Boyle P., Zaridze D. G., Smans M. Descriptive epidemiology of colorectal cancer. Int J Cancer. 1985 Jul 15;36(1):9–18. doi: 10.1002/ijc.2910360103. [DOI] [PubMed] [Google Scholar]
  8. Casnellie J. E., Harrison M. L., Pike L. J., Hellström K. E., Krebs E. G. Phosphorylation of synthetic peptides by a tyrosine protein kinase from the particulate fraction of a lymphoma cell line. Proc Natl Acad Sci U S A. 1982 Jan;79(2):282–286. doi: 10.1073/pnas.79.2.282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Constantinou A., Kiguchi K., Huberman E. Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Res. 1990 May 1;50(9):2618–2624. [PubMed] [Google Scholar]
  10. Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2690–2694. doi: 10.1073/pnas.90.7.2690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoff M. B., Chang W. W., Mak K. M. Effect of estrogen on cell proliferation in colonic mucosa of the mouse. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;35(3):263–273. doi: 10.1007/BF02889166. [DOI] [PubMed] [Google Scholar]
  12. Ingram D., Sanders K., Kolybaba M., Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet. 1997 Oct 4;350(9083):990–994. doi: 10.1016/S0140-6736(97)01339-1. [DOI] [PubMed] [Google Scholar]
  13. Kampman E., Potter J. D., Slattery M. L., Caan B. J., Edwards S. Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control. 1997 Mar;8(2):146–158. doi: 10.1023/a:1018459911147. [DOI] [PubMed] [Google Scholar]
  14. Kuo S. M. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 1996 Dec 20;110(1-2):41–48. doi: 10.1016/s0304-3835(96)04458-8. [DOI] [PubMed] [Google Scholar]
  15. Lamartiniere C. A., Moore J., Holland M., Barnes S. Neonatal genistein chemoprevents mammary cancer. Proc Soc Exp Biol Med. 1995 Jan;208(1):120–123. doi: 10.3181/00379727-208-43843. [DOI] [PubMed] [Google Scholar]
  16. Lee H. P., Gourley L., Duffy S. W., Estéve J., Lee J., Day N. E. Dietary effects on breast-cancer risk in Singapore. Lancet. 1991 May 18;337(8751):1197–1200. doi: 10.1016/0140-6736(91)92867-2. [DOI] [PubMed] [Google Scholar]
  17. Martin P. M., Horwitz K. B., Ryan D. S., McGuire W. L. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology. 1978 Nov;103(5):1860–1867. doi: 10.1210/endo-103-5-1860. [DOI] [PubMed] [Google Scholar]
  18. Messina M. J., Persky V., Setchell K. D., Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer. 1994;21(2):113–131. doi: 10.1080/01635589409514310. [DOI] [PubMed] [Google Scholar]
  19. Ogawara H., Akiyama T., Watanabe S., Ito N., Kobori M., Seoda Y. Inhibition of tyrosine protein kinase activity by synthetic isoflavones and flavones. J Antibiot (Tokyo) 1989 Feb;42(2):340–343. doi: 10.7164/antibiotics.42.340. [DOI] [PubMed] [Google Scholar]
  20. Okura A., Arakawa H., Oka H., Yoshinari T., Monden Y. Effect of genistein on topoisomerase activity and on the growth of [Val 12]Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun. 1988 Nov 30;157(1):183–189. doi: 10.1016/s0006-291x(88)80030-5. [DOI] [PubMed] [Google Scholar]
  21. Pagliacci M. C., Smacchia M., Migliorati G., Grignani F., Riccardi C., Nicoletti I. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer. 1994;30A(11):1675–1682. doi: 10.1016/0959-8049(94)00262-4. [DOI] [PubMed] [Google Scholar]
  22. Potten C. S., Booth C., Chadwick C. A., Evans G. S. A potent stimulator of small intestinal cell proliferation extracted by simple diffusion from intact irradiated intestine: in vitro studies. Growth Factors. 1994;10(1):53–61. doi: 10.3109/08977199409019603. [DOI] [PubMed] [Google Scholar]
  23. Potter J. D., Bostick R. M., Grandits G. A., Fosdick L., Elmer P., Wood J., Grambsch P., Louis T. A. 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 Biomarkers Prev. 1996 Oct;5(10):779–784. [PubMed] [Google Scholar]
  24. Powis G., Kozikowski A. Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. Clin Biochem. 1991 Oct;24(5):385–397. doi: 10.1016/s0009-9120(05)80014-1. [DOI] [PubMed] [Google Scholar]
  25. Quaroni A., May R. J. Establishment and characterizaton of intestinal epithelial cell cultures. Methods Cell Biol. 1980;21B:403–427. [PubMed] [Google Scholar]
  26. Severson R. K., Nomura A. M., Grove J. S., Stemmermann G. N. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. 1989 Apr 1;49(7):1857–1860. [PubMed] [Google Scholar]
  27. Singh S., Paraskeva C., Gallimore P. H., Sheppard M. C., Langman M. J. Differential growth response to oestrogen of premalignant and malignant colonic cell lines. Anticancer Res. 1994 May-Jun;14(3A):1037–1041. [PubMed] [Google Scholar]
  28. Thomas M. L., Xu X., Norfleet A. M., Watson C. S. The presence of functional estrogen receptors in intestinal epithelial cells. Endocrinology. 1993 Jan;132(1):426–430. doi: 10.1210/endo.132.1.8419141. [DOI] [PubMed] [Google Scholar]
  29. Toi M., Mukaida H., Wada T., Hirabayashi N., Toge T., Hori T., Umezawa K. Antineoplastic effect of erbstatin on human mammary and esophageal tumors in athymic nude mice. Eur J Cancer. 1990;26(6):722–724. doi: 10.1016/0277-5379(90)90126-e. [DOI] [PubMed] [Google Scholar]
  30. Troll W., Wiesner R., Shellabarger C. J., Holtzman S., Stone J. P. Soybean diet lowers breast tumor incidence in irradiated rats. Carcinogenesis. 1980 Jun;1(6):469–472. doi: 10.1093/carcin/1.6.469. [DOI] [PubMed] [Google Scholar]
  31. Wang B. H., Ternai B., Polya G. Specific inhibition of cyclic AMP-dependent protein kinase by warangalone and robustic acid. Phytochemistry. 1997 Mar;44(5):787–796. doi: 10.1016/s0031-9422(96)00664-4. [DOI] [PubMed] [Google Scholar]
  32. Wei H., Wei L., Frenkel K., Bowen R., Barnes S. Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein. Nutr Cancer. 1993;20(1):1–12. doi: 10.1080/01635589309514265. [DOI] [PubMed] [Google Scholar]
  33. Welshons W. V., Murphy C. S., Koch R., Calaf G., Jordan V. C. Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol. Breast Cancer Res Treat. 1987 Nov;10(2):169–175. doi: 10.1007/BF01810580. [DOI] [PubMed] [Google Scholar]
  34. Willett W. C. Diet, nutrition, and avoidable cancer. Environ Health Perspect. 1995 Nov;103 (Suppl 8):165–170. doi: 10.1289/ehp.95103s8165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Xu X., Thomas M. L. Estrogen receptor-mediated direct stimulation of colon cancer cell growth in vitro. Mol Cell Endocrinol. 1994 Nov;105(2):197–201. doi: 10.1016/0303-7207(94)90170-8. [DOI] [PubMed] [Google Scholar]
  36. Xu X., Wang H. J., Murphy P. A., Cook L., Hendrich S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J Nutr. 1994 Jun;124(6):825–832. doi: 10.1093/jn/124.6.825. [DOI] [PubMed] [Google Scholar]
  37. Yanagihara K., Ito A., Toge T., Numoto M. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993 Dec 1;53(23):5815–5821. [PubMed] [Google Scholar]
  38. Yoshida M., Sakai T., Hosokawa N., Marui N., Matsumoto K., Fujioka A., Nishino H., Aoike A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett. 1990 Jan 15;260(1):10–13. doi: 10.1016/0014-5793(90)80053-l. [DOI] [PubMed] [Google Scholar]
  39. Zava D. T., Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer. 1997;27(1):31–40. doi: 10.1080/01635589709514498. [DOI] [PubMed] [Google Scholar]

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