Skip to main content
Log in

Mechanisms of Cancer Chemoprevention by Soy Isoflavone Genistein

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Diet has been implicated to play an important role in cancers. Epidemiological studies have revealed that Asians, who consume a traditional diet high in soy products, have relatively low incidences of breast and prostate cancers, while the incidences are much higher in the Western world. Asians who immigrate to the United States and adopt a Western diet are at higher risks of breast and prostate cancers. Soy isoflavones have received much attention as dietary components having an important role in reducing breast and prostate cancers. Genistein, one of the predominant soy isoflavones, has been shown to inhibit the growth of cancer cells through the modulation of genes that are related to the homeostatic control of cell cycle and apoptosis. It has been found that genistein inhibits the activation of the nuclear transcription factor, NF-κB and Akt signaling pathway, both of which are known to maintain a balance between cell survival and programmed cell death (apoptosis). Genistein is known to have anti-oxidant property, and commonly known as phytoestrogen, which targets estrogen and androgen-mediated signaling pathway in the processes of carcinogenesis. Moreover, genistein is also found to be a potent inhibitor of angiogenesis and metastasis. Hence, significant advances have been made, both by in vitro and in vivo studies showing that genistein is a promising agent for cancer chemoprevention and/or treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet R, Sigman CC: Chemopreventive drug development: Perspectives and progress. Cancer Epidemiol Biomarkers Prev 3: 85–98, 1994

    Google Scholar 

  2. Adlercreutz CH, Goldin BR, Gorbach SL, Hockerstedt KA, Watanabe S, Hamalainen EK, Markkanen MH, Makela TH, Wahala KT, Adlercreutz T: Soybean phytoestrogen intake and cancer risk. J Nutr 125: 757S–770S, 1995

    Google Scholar 

  3. Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE: Dietary effects on breast-cancer risk in Singapore. Lancet 337: 1197–1200, 1991

    Google Scholar 

  4. Adlercreutz H, Honjo H, Higashi A, Fotsis T, Hamalainen E, Hasegawa T, Okada H: Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr 54: 1093–1100, 1991

    Google Scholar 

  5. Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS: Nutritional and socioeconomic factors in relation to prostate cancer mortality: A cross-national study. J Natl Cancer Inst 90: 1637–1647, 1998

    Google Scholar 

  6. Jacobsen BK, Knutsen SF, Fraser GE: Does high soy milk intake reduce prostate cancer incidence? The Adventist health study (United States). Cancer Causes Control 9: 553–557, 1998

    Google Scholar 

  7. Adlercreutz H: Does fiber-rich food containing animal lignan precursors protect against both colon and breast cancer? An extension of the 'fiber hypothesis'. Gastroenterology 86: 761–764, 1984

    Google Scholar 

  8. Davis JN, Singh B, Bhuiyan M, Sarkar FH: Genistein-induced upregulation of p21WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 32: 123–131, 1998

    Google Scholar 

  9. Li Y, Upadhyay S, Bhuiyan M, Sarkar FH: Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18: 3166–3172, 1999

    Google Scholar 

  10. Li Y, Bhuiyan M, Sarkar FH: Induction of apoptosis and inhibition of c-erbB-2 inMDA-MB-435 cells by genistein. Int J Oncol 15: 525–533, 1999

    Google Scholar 

  11. Lian F, Bhuiyan M, Li YW, Wall N, Kraut M, Sarkar FH: Genistein-induced G2-M arrest, p21WAF1 upregulation, and apoptosis in a non-small-cell lung cancer cell line. Nutr Cancer 31: 184–191, 1998

    Google Scholar 

  12. Alhasan SA, Pietrasczkiwicz H, Alonso MD, Ensley J, Sarkar FH: Genistein-induced cell cycle arrest and apoptosis in a head and neck squamous cell carcinoma cell line. Nutr Cancer 34: 12–19, 1999

    Google Scholar 

  13. Upadhyay S, Neburi M, Chinni SR, Alhasan S, Miller F, Sarkar FH: Differential sensitivity of normal and malignant breast epithelial cells to genistein is partly mediated by p21(WAF1). Clin Cancer Res 7: 1782–1789, 2001

    Google Scholar 

  14. Spinozzi F, Pagliacci MC, Migliorati G, Moraca R, Grignani F, Riccardi C, Nicoletti I: The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. Leuk Res 18: 431–439, 1994

    Google Scholar 

  15. Constantinou A, Huberman E: Genistein as an inducer of tumor cell differentiation: Possible mechanisms of action. Proc Soc Exp Biol Med 208: 109–115, 1995

    Google Scholar 

  16. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der BB, Gustafsson JA: Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139: 4252–4263, 1998

    Google Scholar 

  17. Adlercreutz H, Markkanen H, Watanabe S: Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342: 1209–1210, 1993

    Google Scholar 

  18. Knight DC, Eden JA: A review of the clinical effects of phytoestrogens. Obstet Gynecol 87: 897–904, 1996

    Google Scholar 

  19. Mills PK, Beeson WL, Phillips RL, Fraser GE: Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer 64: 598–604, 1989

    Google Scholar 

  20. Zava DT, Dollbaum CM, Blen M: Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 217: 369–378, 1998

    Google Scholar 

  21. Martin PM, Horwitz KB, Ryan DS, McGuire WL: Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103: 1860–1867, 1978

    Google Scholar 

  22. Peterson G, Barnes S: 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, 1991

    Google Scholar 

  23. 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 262: 5592–5595, 1987

    Google Scholar 

  24. Hunter T: A thousand and one protein kinases. Cell 50: 823–829, 1987

    Google Scholar 

  25. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212, 1990

    Google Scholar 

  26. 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 157: 183–189, 1988

    Google Scholar 

  27. Evans BA, Griffiths K, Morton MS: Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol 147: 295–302, 1995

    Google Scholar 

  28. Huang J, Nasr M, Kim Y, Matthews HR: Genistein inhibits protein histidine kinase. J Biol Chem 267: 15511–15515, 1992

    Google Scholar 

  29. Ruiz-Larrea MB, Mohan AR, Paganga G, Miller NJ, Bolwell GP, Rice-Evans CA: Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res 26: 63–70, 1997

    Google Scholar 

  30. Zhou Y, Lee AS: Mechanism for the suppression of the mammalian stress response by genistein, an anticancer phytoestrogen from soy. J Natl Cancer Inst 90: 381–388, 1998

    Google Scholar 

  31. Wu M, Lee H, Bellas RE, Schauer SL, Arsura M, Katz D, FitzGerald MJ, Rothstein TL, Sherr DH, Sonenshein GE: Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J 15: 4682–4690, 1996

    Google Scholar 

  32. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM: Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789, 1996

    Google Scholar 

  33. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC: Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318–1321, 1998

    Google Scholar 

  34. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868, 1999

    Google Scholar 

  35. Kyle E, Neckers L, Takimoto C, Curt G, Bergan R: Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity. Mol Pharmacol 51: 193–200, 1997

    Google Scholar 

  36. Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, Schweigerer L: Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125: 790S–797S, 1995

    Google Scholar 

  37. Barnes S: Effect of genistein on in vitro and in vivo models of cancer. J Nutr 125: 777S–783S, 1995

    Google Scholar 

  38. 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 50: 2618–2624, 1990

    Google Scholar 

  39. Peterson G, Barnes S: Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 22: 335–345, 1993

    Google Scholar 

  40. Peterson G, Barnes S: Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ 7: 1345–1351, 1996

    Google Scholar 

  41. Buckley AR, Buckley DJ, Gout PW, Liang H, Rao YP, Blake MJ: Inhibition by genistein of prolactin-induced Nb2 lymphoma cell mitogenesis. Mol Cell Endocrinol 98: 17–25, 1993

    Google Scholar 

  42. Schweigerer L, Christeleit K, Fleischmann G, Adlercreutz H, Wahala K, Hase T, Schwab M, Ludwig R, Fotsis T: Identification in human urine of a natural growth inhibitor for cells derived from solid paediatric tumours. Eur J Clin Invest 22: 260–264, 1992

    Google Scholar 

  43. Matsukawa Y, Marui N, Sakai T, Satomi Y, Yoshida M, Matsumoto K, Nishino H, Aoike A: Genistein arrests cell cycle progression at G2-M. Cancer Res 53: 1328–1331, 1993

    Google Scholar 

  44. Pagliacci MC, 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 30A: 1675–1682, 1994

    Google Scholar 

  45. Casagrande F, Darbon JM: p21CIP1 is dispensable for the G2 arrest caused by genistein in human melanoma cells. Exp Cell Res 258: 101–108, 2000

    Google Scholar 

  46. Kuzumaki T, Kobayashi T, Ishikawa K: Genistein induces p21(Cip1/WAF1) expression and blocks the G1 to S phase transition in mouse fibroblast and melanoma cells. Biochem Biophys Res Commun 251: 291–295, 1998

    Google Scholar 

  47. Lian F, Li Y, Bhuiyan M, Sarkar FH: p53-independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer 33: 125–131, 1999

    Google Scholar 

  48. Alhasan SA, Ensley JF, Sarkar FH: Genistein induced molecular changes in a squamous cell carcinoma of the head and neck cell line. Int J Oncol 16: 333–338, 2000

    Google Scholar 

  49. Chiarugi V, Magnelli L, Cinelli M, Basi G: Apoptosis and the cell cycle. Cell Mol Biol Res 40: 603–612, 1994

    Google Scholar 

  50. Huang P, Ballal K, Plunkett W: Biochemical characterization of the protein activity responsible for high molecular weight DNA fragmentation during drug-induced apoptosis. Cancer Res 57: 3407–3414, 1997

    Google Scholar 

  51. Fisher DE: Apoptosis in cancer therapy: Crossing the threshold. Cell 78: 539–542, 1994

    Google Scholar 

  52. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC: Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371: 346–347, 1994

    Google Scholar 

  53. Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM: Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81: 801–809, 1995

    Google Scholar 

  54. Darmon AJ, Nicholson DW, Bleackley RC: Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377: 446–448, 1995

    Google Scholar 

  55. Philpott NJ, Turner AJ, Scopes J, Westby M, Marsh JC, Gordon-Smith EC, Dalgleish AG, Gibson FM: The use of 7-amino actinomycin D in identifying apoptosis: Simplicity of use and broad spectrum of application compared with other techniques. Blood 87: 2244–2251, 1996

    Google Scholar 

  56. Park JR, Hockenbery DM: BCL-2, a novel regulator of apoptosis. J Cell Biochem 60: 12–17, 1996

    Google Scholar 

  57. Findley HW, Gu L, Yeager AM, Zhou M: Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. Blood 89: 2986–2993, 1997

    Google Scholar 

  58. Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen DE: Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 262: 1274–1277, 1993

    Google Scholar 

  59. Salomons GS, Brady HJ, Verwijs-Janssen M, Van Den Berg JD, Hart AA, Van Den BH, Behrendt H, Hahlen K, Smets LA: The Bax alpha: Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int J Cancer 71: 959–965, 1997

    Google Scholar 

  60. Vogelstein B, Kinzler KW: p53 function and dysfunction. Cell 70: 523–526, 1992

    Google Scholar 

  61. el Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825, 1993

    Google Scholar 

  62. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816, 1993

    Google Scholar 

  63. Agarwal ML, Agarwal A, Taylor WR, Stark GR: p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA 92: 8493–8497, 1995

    Google Scholar 

  64. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D: p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704, 1993

    Google Scholar 

  65. Shao ZM, Alpaugh ML, Fontana JA, Barsky SH: Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem 69: 44–54, 1998

    Google Scholar 

  66. Wang TT, Sathyamoorthy N, Phang JM: Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17: 271–275, 1996

    Google Scholar 

  67. Wang C, Kurzer MS: Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr Cancer 28: 236–247, 1997

    Google Scholar 

  68. Papavassiliou AG: Transcription factors: Structure, function, and implication in malignant growth. Anticancer Res 15: 891–894, 1995

    Google Scholar 

  69. Sen R, Baltimore D: Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47: 921–928, 1986

    Google Scholar 

  70. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S: Rel/NF-kappa B/I kappa B family: Intimate tales of association and dissociation. Genes Dev 9: 2723–2735, 1995

    Google Scholar 

  71. Thanos D, Maniatis T: NF-kappa B: A lesson in family values. Cell 80: 529–532, 1995

    Google Scholar 

  72. Ghosh G, van Duyne G, Ghosh S, Sigler PB: Structure of NF-kappa B p50 homodimer bound to a kappa B site. Nature 373: 303–310, 1995

    Google Scholar 

  73. Muller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC: Structure of the NF-kappa B p50 homodimer bound to DNA. Nature 373: 311–317, 1995

    Google Scholar 

  74. Muller CW, Harrison SC: The structure of the NF-kappa B p50:DNA-complex: A starting point for analyzing the Rel family. FEBS Lett 369: 113–117, 1995

    Google Scholar 

  75. Chen ZJ, Parent L, Maniatis T: Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84: 853–862, 1996

    Google Scholar 

  76. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T: Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 9: 1586–1597, 1995

    Google Scholar 

  77. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA: Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J 14: 2876–2883, 1995

    Google Scholar 

  78. Pahl HL, Baeuerle PA: Control of gene expression by proteolysis. Curr Opin Cell Biol 8: 340–347, 1996

    Google Scholar 

  79. Lenardo MJ, Baltimore D: NF-kappa B: A pleiotropic mediator of inducible and tissue-specific gene control. Cell 58: 227–229, 1989

    Google Scholar 

  80. Baldwin AS Jr.: The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14: 649–683, 1996

    Google Scholar 

  81. Beg AA, Baltimore D: An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274: 782–784, 1996

    Google Scholar 

  82. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr.: NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281: 1680–1683, 1998

    Google Scholar 

  83. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D: Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376: 167–170, 1995

    Google Scholar 

  84. Davis JN, Kucuk O, Sarkar FH: Genistein inhibits NF-kappa Bactivation in prostate cancer cells. Nutr Cancer 35: 167–174, 1999

    Google Scholar 

  85. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U: Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485–1488, 1995

    Google Scholar 

  86. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M: A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388: 548–554, 1997

    Google Scholar 

  87. Jamaluddin M, Casola A, Garofalo RP, Han Y, Elliott T, Ogra PL, Brasier AR: The major component of IkappaBalpha proteolysis occurs independently of the proteasome pathway in respiratory syncytial virus-infected pulmonary epithelial cells. J Virol 72: 4849–4857, 1998

    Google Scholar 

  88. Zandi E, Chen Y, Karin M: Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: Discrimination between free and NF-kappaB-bound substrate. Science 281: 1360–1363, 1998

    Google Scholar 

  89. Karin M, Delhase M: The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signalling. Semin Immunol 12: 85–98, 2000

    Google Scholar 

  90. Lee FS, Peters RT, Dang LC, Maniatis T: MEKK1activates both IkappaB kinase alpha and IkappaB kinase beta. Proc Natl Acad Sci USA 95: 9319–9324, 1998

    Google Scholar 

  91. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K: Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci USA 95: 3537–3542, 1998

    Google Scholar 

  92. Franke TF, Kaplan DR, Cantley LC: PI3K: Downstream AKTion blocks apoptosis. Cell 88: 435–437, 1997

    Google Scholar 

  93. Burgering BM, Coffer PJ: Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376: 599–602, 1995

    Google Scholar 

  94. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN: The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81: 727–736, 1995

    Google Scholar 

  95. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA: Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541–6551, 1996

    Google Scholar 

  96. Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ: Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286: 1738–1741, 1999

    Google Scholar 

  97. Romashkova JA, Makarov SS: NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401: 86–90, 1999

    Google Scholar 

  98. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401: 82–85, 1999

    Google Scholar 

  99. Sarkar, et al.: Our unpublished data

  100. Yang CH, Murti A, Pfeffer SR, Kim JG, Donner DB, Pfeffer LM: Interferon alpha/beta promotes cell survival by activating nuclear factor kappa B through phosphatidylinositol 3-kinase and Akt. J Biol Chem 276: 13756–13761, 2001

    Google Scholar 

  101. Richter F, Huang HF, Li MT, Danielpour D, Wang SL, Irwin RJ Jr.: Retinoid and androgen regulation of cell growth, epidermal growth factor and retinoic acid receptors in normal and carcinoma rat prostate cells. Mol Cell Endocrinol 153: 29–38, 1999

    Google Scholar 

  102. Montgomery JS, Price DK, Figg WD: The androgen receptor gene and its influence on the development and progression of prostate cancer. J Pathol 195: 138–146, 2001

    Google Scholar 

  103. Kupelian P, Katcher J, Levin H, Zippe C, Klein E: Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 48: 249–260, 1996

    Google Scholar 

  104. Luke MC, Coffey DS: Human androgen receptor binding to the androgen response element of prostate specific antigen. J Androl 15: 41–51, 1994

    Google Scholar 

  105. Sato N, Gleave ME, Bruchovsky N, Rennie PS, Goldenberg SL, Lange PH, Sullivan LD: Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol 58: 139–146, 1996

    Google Scholar 

  106. Davis JN, Muqim N, Bhuiyan M, Kucuk O, Pienta KJ, Sarkar FH: Inhibition of prostate specific antigen expression by genistein in prostate cancer cells. Int J Oncol 16: 1091–1097, 2000

    Google Scholar 

  107. Sarkar, et al.: Our unpublished data

  108. Pike AC, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, Ljunggren J, Gustafsson JA, Carlquist M: Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 18: 4608–4618, 1999

    Google Scholar 

  109. Lacroix H, Iglehart JD, Skinner MA, Kraus MH: Overexpression of erbB-2 or EGF receptor proteins present in early stage mammary carcinoma is detected simultaneously in matched primary tumors and regional metastases. Oncogene 4: 145–151, 1989

    Google Scholar 

  110. Yu D, Wang SS, Dulski KM, Tsai CM, Nicolson GL, Hung MC: c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res 54: 3260–3266, 1994

    Google Scholar 

  111. Yu D, Matin A, Xia W, Sorgi F, Huang L, Hung MC: Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. Oncogene 11: 1383–1388, 1995

    Google Scholar 

  112. Tan M, Yao J, Yu D: Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res 57: 1199–1205, 1997

    Google Scholar 

  113. Muller D, Breathnach R, Engelmann A, Millon R, Bronner G, Flesch H, Dumont P, Eber M, Abecassis J: Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int J Cancer 48: 550–556, 1991

    Google Scholar 

  114. Liotta LA, Stetler-Stevenson WG: Metalloproteinases and cancer invasion. Semin Cancer Biol 1: 99–106, 1990

    Google Scholar 

  115. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  116. Li Y, Bhuiyan M, Alhasan S, Senderowicz AM, Sarkar FH: Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. Clin Cancer Res 6: 223–229, 2000

    Google Scholar 

  117. Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, Schweigerer L: Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125: 790S–797S, 1995

    Google Scholar 

  118. Roberts AB, Flanders KC, Heine UI, Jakowlew S, Kondaiah P, Kim SJ, Sporn MB: Transforming growth factor-beta: Multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 327: 145–154, 1990

    Google Scholar 

  119. Kim H, Peterson TG, Barnes S: Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor beta signaling pathways. Am J Clin Nutr 68: 1418S–1425S, 1998

    Google Scholar 

  120. 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 20: 1–12, 1993

    Google Scholar 

  121. Bostwick DG, Alexander EE, Singh R, Shan A, Qian J, Santella RM, Oberley LW, Yan T, Zhong W, Jiang X, Oberley TD: Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Cancer 89: 123–134, 2000

    Google Scholar 

  122. van Rossen ME, Sluiter W, Bonthuis F, Jeekel H, Marquet RL, van Eijck CH: Scavenging of reactive oxygen species leads to diminished peritoneal tumor recurrence. Cancer Res 60: 5625–5629, 2000

    Google Scholar 

  123. Nagao N, Nakayama T, Etoh T, Saiki I, Miwa N: Tumor invasion is inhibited by phosphorylated ascorbate via enrichment of intracellular vitamin C and decreasing of oxidative stress. J Cancer Res Clin Oncol 126: 511–518, 2000

    Google Scholar 

  124. Nonaka Y, Iwagaki H, Kimura T, Fuchimoto S, Orita K: Effect of reactive oxygen intermediates on the in vitro invasive capacity of tumor cells and liver metastasis in mice. Int J Cancer 54: 983–986, 1993

    Google Scholar 

  125. Kameoka S, Leavitt P, Chang C, Kuo SM: Expression of antioxidant proteins in human intestinal Caco-2 cells treated with dietary flavonoids. Cancer Lett 146: 161–167, 1999

    Google Scholar 

  126. Toledano MB, Leonard WJ: Modulation of transcription factor NF-kappa B binding activity by oxidation-reduction in vitro. Proc Natl Acad Sci USA 88: 4328–4332, 1991

    Google Scholar 

  127. Dudek EJ, Shang F, Taylor A: H2O2-mediated oxidative stress activates NF-kappaB in lens epithelial cells. Free Radic Biol Med 31: 651–658, 2001

    Google Scholar 

  128. Davis JN, Kucuk O, Djuric Z, Sarkar FH: Soy isoflavone supplementation in healthy men prevents NF-kappaB activation by TNF-alpha in blood lymphocytes. Free Radic Biol Med 30: 1293–1302, 2001

    Google Scholar 

  129. Sharma OP, Adlercreutz H, Strandberg JD, Zirkin BR, Coffey DS, Ewing LL: Soy of dietary source plays a preventive role against the pathogenesis of prostatitis in rats. J Steroid Biochem Mol Biol 43: 557–564, 1992

    Google Scholar 

  130. Onozawa M, Kawamori T, Baba M, Fukuda K, Toda T, Sato H, Ohtani M, Akaza H, Sugimura T, Wakabayashi K: Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats. Jpn J Cancer Res 90: 393–398, 1999

    Google Scholar 

  131. Landstrom M, Zhang JX, Hallmans G, Aman P, Bergh A, Damber JE, Mazur W, Wahala K, Adlercreutz H: Inhibitory effects of soy and rye diets on the development of Dunning R3327 prostate adenocarcinoma in rats. Prostate 36: 151–161, 1998

    Google Scholar 

  132. Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, Clinton SK: Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 129: 1628–1635, 1999

    Google Scholar 

  133. Li D, Yee JA, McGuire MH, Murphy PA, Yan L: Soybean isoflavones reduce experimental metastasis in mice. J Nutr 129: 1075–1078, 1999

    Google Scholar 

  134. Lamartiniere CA, Moore JB, Brown NM, Thompson R, Hardin MJ, Barnes S: Genistein suppresses mammary cancer in rats. Carcinogenesis 16: 2833–2840, 1995

    Google Scholar 

  135. Uckun FM, Evans WE, Forsyth CJ, Waddick KG, Ahlgren LT, Chelstrom LM, Burkhardt A, Bolen J, Myers DE: Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science 267: 886–891, 1995

    Google Scholar 

  136. Sarkar, et al.: Our unpublished data

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sarkar, F.H., Li, Y. Mechanisms of Cancer Chemoprevention by Soy Isoflavone Genistein. Cancer Metastasis Rev 21, 265–280 (2002). https://doi.org/10.1023/A:1021210910821

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021210910821

Navigation