Role of Phytoestrogens in Cancer Therapy

Abstract

Cancer is a leading cause of death worldwide, and the numbers of new cancer cases are expected to continue to rise. The main goals of cancer therapy include removing the primary tumor, preventing the spread of distant metastases, and improving survival and quality of life for the patients. To attain these goals of cancer therapy, the combination of different chemotherapeutics, as opposed to the conventional single-agent treatment, is an emerging area of research. Given the potential risks of drug toxicity in such treatment, the focus is to have a second compound that increases the anticancer potential of the primary agent but which reduces toxicity. There is an ever growing interest in treatment with natural compounds, such as plant phytoestrogens, as an adjuvant cancer therapy along with conventional cancer therapy. The question remains whether or not adding these compounds to the cancer therapy regimen as a second agent would be beneficial, and if they are safe to be used among cancer patients. The current literature suggests that phytoestrogen treatment is capable of inducing G2/M cell cycle arrest in a number of cancer cell lines, as well as upregulating cell cycle inhibitory molecules. Phytoestrogen therapy has been shown to inhibit inflammation, angiogenesis and metastases in various in vivo tumor models, and pronounced benefits have been observed when combined with radiation therapy. The lack of side effects from phase I and II clinical trials of phytoestrogens in cancer therapy points towards their safety, but to further understand their added benefit clinical studies with large sample sizes are required. We have reviewed the recent research studies in these areas in an attempt to find evidence for their role in cancer therapy as well as safety.

phytoestrogens - cancer therapy - cell cycle regulation - inflammation - angiogenesis - metastasis

References

• 1 Russo I H, Russo J. Role of hormones in mammary cancer initiation and progression.  J Mammary Gland Biol Neoplasia. 1998;  3 49-61
• 2 Huggins C H C. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate.  Cancer Res. 1941;  1 293-297
• 3 Fritsch M, Jordan V C. Long-term tamoxifen therapy for the treatment of breast cancer.  Cancer Control. 1994;  1 356-366
• 4 Miller W R. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer.  Semin Oncol. 2003;  30 (4 Suppl. 14) 3-11
• 5 Lieberman R. Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development.  Urology. 2001;  58 (2 Suppl. 1) 83-90
• 6 Lobo R A. Benefits and risks of estrogen replacement therapy.  Am J Obstet Gynecol. 1995;  173 982-989
• 7 Rossouw J E, Anderson G L, Prentice R L, LaCroix A Z, Kooperberg C, Stefanick M L, Jackson R D, Beresford S A, Howard B V, Johnson K C, Kotchen J M, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial.  JAMA. 2002;  288 321-333
• 8 Pritchard K I. Breast cancer prevention with selective estrogen receptor modulators: a perspective.  Ann NY Acad Sci. 2001;  949 89-98
• 9 Cummings S R, Eckert S, Krueger K A, Grady D, Powles T J, Cauley J A, Norton L, Nickelsen T, Bjarnason N H, Morrow M, Lippman M E, Black D, Glusman J E, Costa A, Jordan V C. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation.  JAMA. 1999;  281 2189-2197
• 10 St Clair R W. Estrogens and atherosclerosis: phytoestrogens and selective estrogen receptor modulators.  Curr Opin Lipidol. 1998;  9 457-463
• 11 Oseni T, Patel R, Pyle J, Jordan V C. Selective estrogen receptor modulators and phytoestrogens.  Planta Med. 2008;  74 1656-1665
• 12 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;  262 5592-5595
• 13 Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products.  Lymphat Res Biol. 2010;  8 89-98
• 14 Davis J N, Kucuk O, Sarkar F H. Genistein inhibits NF-kappa B activation in prostate cancer cells.  Nutr Cancer. 1999;  35 167-174
• 15 Krazeisen A, Breitling R, Moller G, Adamski J. Phytoestrogens inhibit human 17beta-hydroxysteroid dehydrogenase type 5.  Mol Cell Endocrinol. 2001;  171 151-162
• 16 Rice S, Mason H D, Whitehead S A. Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells.  J Steroid Biochem Mol Biol. 2006;  101 216-225
• 17 Dang Z C, Audinot V, Papapoulos S E, Boutin J A, Lowik C W. Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein.  J Biol Chem. 2003;  278 962-967
• 18 Chacko B K, Chandler R T, Mundhekar A, Khoo N, Pruitt H M, Kucik D F, Parks D A, Kevil C G, Barnes S, Patel R P. Revealing anti-inflammatory mechanisms of soy isoflavones by flow: modulation of leukocyte-endothelial cell interactions.  Am J Physiol Heart Circ Physiol. 2005;  289 H908-H915
• 19 Wu A H, Ziegler R G, Horn-Ross P L, Nomura A M, West D W, Kolonel L N, Rosenthal J F, Hoover R N, Pike M C. Tofu and risk of breast cancer in Asian-Americans.  Cancer Epidemiol Biomarkers Prev. 1996;  5 901-906
• 20 Kurahashi N, Iwasaki M, Sasazuki S, Otani T, Inoue M, Tsugane S. Soy product and isoflavone consumption in relation to prostate cancer in Japanese men.  Cancer Epidemiol Biomarkers Prev. 2007;  16 538-545
• 21 Busby M G, Jeffcoat A R, Bloedon L T, Koch M A, Black T, Dix K J, Heizer W D, Thomas B F, Hill J M, Crowell J A, Zeisel S H. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men.  Am J Clin Nutr. 2002;  75 126-136
• 22 Bloedon L T, Jeffcoat A R, Lopaczynski W, Schell M J, Black T M, Dix K J, Thomas B F, Albright C, Busby M G, Crowell J A, Zeisel S H. Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women.  Am J Clin Nutr. 2002;  76 1126-1137
• 23 Smeds A I, Eklund P C, Sjoholm R E, Willfor S M, Nishibe S, Deyama T, Holmbom B R. Quantification of a broad spectrum of lignans in cereals, oilseeds, and nuts.  J Agric Food Chem. 2007;  55 1337-1346
• 24 Smeds A I, Jauhiainen L, Tuomola E, Peltonen-Sainio P. Characterization of variation in the lignan content and composition of winter rye, spring wheat, and spring oat.  J Agric Food Chem. 2009;  57 5837-5842
• 25 Clavel T, Dore J, Blaut M. Bioavailability of lignans in human subjects.  Nutr Res Rev. 2006;  19 187-196
• 26 Duncan A M, Phipps W R, Kurzer M S. Phyto-oestrogens.  Best Pract Res Clin Endocrinol Metab. 2003;  17 253-271
• 27 Wiseman H. The bioavailability of non-nutrient plant factors: dietary flavonoids and phyto-oestrogens.  Proc Nutr Soc. 1999;  58 139-146
• 28 USDA Database for Isoflavone Content of Selected Foods. Release 2.0. http://www.ars.usda.gov/Services/docs.htm?docid=6382 Accessed November 12, 2009
• 29 Sfakianos J, Coward L, Kirk M, Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats.  J Nutr. 1997;  127 1260-1268
• 30 Kano M, Takayanagi T, Harada K, Sawada S, Ishikawa F. Bioavailability of isoflavones after ingestion of soy beverages in healthy adults.  J Nutr. 2006;  136 2291-2296
• 31 Hedlund T E, Maroni P D, Ferucci P G, Dayton R, Barnes S, Jones K, Moore R, Ogden L G, Wahala K, Sackett H M, Gray K J. Long-term dietary habits affect soy isoflavone metabolism and accumulation in prostatic fluid in Caucasian men.  J Nutr. 2005;  135 1400-1406
• 32 Sorrentino V. The cell cycle. Pusztai L, Lewis CE, Yap E Cell proliferation in cancer, regulatory mechanisms of neoplastic growth. Oxford; Oxford Medical Publications 1995: 25-41
• 33 Singh A V, Franke A A, Blackburn G L, Zhou J R. Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis.  Cancer Res. 2006;  66 1851-1858
• 34 Yashar C M, Spanos W J, Taylor D D, Gercel-Taylor C. Potentiation of the radiation effect with genistein in cervical cancer cells.  Gynecol Oncol. 2005;  99 199-205
• 35 Raffoul J J, Wang Y, Kucuk O, Forman J D, Sarkar F H, Hillman G G. Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest.  BMC Cancer. 2006;  6 107
• 36 Sasamura H, Takahashi A, Miyao N, Yanase M, Masumori N, Kitamura H, Itoh N, Tsukamoto T. Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma.  Br J Cancer. 2002;  86 768-773
• 37 Darby I A, Hewitson T D. Fibroblast differentiation in wound healing and fibrosis.  Int Rev Cytol. 2007;  257 143-179
• 38 Coussens L M, Werb Z. Inflammation and cancer.  Nature. 2002;  420 860-867
• 39 Ditsworth D, Zong W X. NF-kappaB: key mediator of inflammation-associated cancer.  Cancer Biol Ther. 2004;  3 1214-1216
• 40 Sandler R S, Halabi S, Baron J A, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas J M, Karp D D, Loprinzi C L, Steinbach G, Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.  N Engl J Med. 2003;  348 883-890
• 41 Chan A T, Giovannucci E L, Meyerhardt J A, Schernhammer E S, Curhan G C, Fuchs C S. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.  JAMA. 2005;  294 914-923
• 42 Chan A T. Aspirin, non-steroidal anti-inflammatory drugs and colorectal neoplasia: future challenges in chemoprevention.  Cancer Causes Control. 2003;  14 413-418
• 43 Flossmann E, Rothwell P M. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.  Lancet. 2007;  369 1603-1613
• 44 Krenn L, Paper D H. Inhibition of angiogenesis and inflammation by an extract of red clover (Trifolium pratense L.).  Phytomedicine. 2009;  16 1083-1088
• 45 Hwang J T, Lee Y K, Shin J I, Park O J. Anti-inflammatory and anticarcinogenic effect of genistein alone or in combination with capsaicin in TPA-treated rat mammary glands or mammary cancer cell line.  Ann NY Acad Sci. 2009;  1171 415-420
• 46 Paradkar P N, Blum P S, Berhow M A, Baumann H, Kuo S M. Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine.  Cancer Lett. 2004;  215 21-28
• 47 Seibel J, Molzberger A F, Hertrampf T, Laudenbach-Leschowski U, Diel P. Oral treatment with genistein reduces the expression of molecular and biochemical markers of inflammation in a rat model of chronic TNBS-induced colitis.  Eur J Nutr. 2009;  48 213-220
• 48 Ko K P, Park S K, Cho L Y, Gwack J, Yang J J, Shin A, Kim C S, Kim Y, Kang D, Chang S H, Shin H R, Yoo K Y. Soybean product intake modifies the association between interleukin-10 genetic polymorphisms and gastric cancer risk.  J Nutr. 2009;  139 1008-1012
• 49 Huang Y, Cao S, Nagamani M, Anderson K E, Grady J J, Lu L J. Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones.  J Clin Endocrinol Metab. 2005;  90 3956-3962
• 50 Battegay E J. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects.  J Mol Med. 1995;  73 333-346
• 51 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nat Med. 1995;  1 27-31
• 52 Kiriakidis S, Hogemeier O, Starcke S, Dombrowski F, Hahne J C, Pepper M, Jha H C, Wernert N. Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay.  Br J Nutr. 2005;  93 317-323
• 53 Sasamura H, Takahashi A, Yuan J, Kitamura H, Masumori N, Miyao N, Itoh N, Tsukamoto T. Antiproliferative and antiangiogenic activities of genistein in human renal cell carcinoma.  Urology. 2004;  64 389-393
• 54 Farina H G, Pomies M, Alonso D F, Gomez D E. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer.  Oncol Rep. 2006;  16 885-891
• 55 Bergman J M, Thompson L U, Dabrosin C. Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo.  Clin Cancer Res. 2007;  13 1061-1067
• 56 Fidler I J. Cancer metastasis.  Br Med Bull. 1991;  47 157-177
• 57 Miura D, Saarinen N M, Miura Y, Santti R, Yagasaki K. Hydroxymatairesinol and its mammalian metabolite enterolactone reduce the growth and metastasis of subcutaneous AH109A hepatomas in rats.  Nutr Cancer. 2007;  58 49-59
• 58 Buchler P, Gukovskaya A S, Mouria M, Buchler M C, Buchler M W, Friess H, Pandol S J, Reber H A, Hines O J. Prevention of metastatic pancreatic cancer growth in vivo by induction of apoptosis with genistein, a naturally occurring isoflavonoid.  Pancreas. 2003;  26 264-273
• 59 Li Y, Kucuk O, Hussain M, Abrams J, Cher M L, Sarkar F H. Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer.  Cancer Res. 2006;  66 4816-4825
• 60 Vantyghem S A, Wilson S M, Postenka C O, Al-Katib W, Tuck A B, Chambers A F. Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model.  Cancer Res. 2005;  65 3396-3403
• 61 Raffoul J J, Banerjee S, Che M, Knoll Z E, Doerge D R, Abrams J, Kucuk O, Sarkar F H, Hillman G G. Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model.  Int J Cancer. 2007;  120 2491-2498
• 62 Hillman G G, Wang Y, Kucuk O, Che M, Doerge D R, Yudelev M, Joiner M C, Marples B, Forman J D, Sarkar F H. Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model.  Mol Cancer Ther. 2004;  3 1271-1279
• 63 Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto C H, Helenowski I, Pelling J C, Bergan R C. Dietary genistein inhibits metastasis of human prostate cancer in mice.  Cancer Res. 2008;  68 2024-2032
• 64 ClinicalTrials.gov. http://www.clinicaltrials.gov Accessed April 07, 2010
• 65 Chuang S E, Yeh P Y, Lu Y S, Lai G M, Liao C M, Gao M, Cheng A L. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells.  Biochem Pharmacol. 2002;  63 1709-1716
• 66 Li Y, Ahmed F, Ali S, Philip P A, Kucuk O, Sarkar F H. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.  Cancer Res. 2005;  65 6934-6942
• 67 Gustin J A, Ozes O N, Akca H, Pincheira R, Mayo L D, Li Q, Guzman J R, Korgaonkar C K, Donner D B. Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation.  J Biol Chem. 2004;  279 1615-1620
• 68 Hillman G G, Wang Y, Che M, Raffoul J J, Yudelev M, Kucuk O, Sarkar F H. Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model.  BMC Cancer. 2007;  7 4
• 69 Boyapati S M, Shu X O, Ruan Z X, Dai Q, Cai Q, Gao Y T, Zheng W. Soyfood intake and breast cancer survival: a followup of the Shanghai Breast Cancer Study.  Breast Cancer Res Treat. 2005;  92 11-17
• 70 De L M. Safety issues of soy phytoestrogens in breast cancer patients.  J Clin Oncol. 2002;  20 3040-3041
• 71 Velentzis L S, Woodside J V, Cantwell M M, Leathem A J, Keshtgar M R. Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? What clinicians need to know.  Eur J Cancer. 2008;  44 1799-1806
• 72 Lammersfeld C A, King J, Walker S, Vashi P G, Grutsch J F, Lis C G, Gupta D. Prevalence, sources, and predictors of soy consumption in breast cancer.  Nutr J. 2009;  8 2
• 73 Messina M J, Loprinzi C L. Soy for breast cancer survivors: a critical review of the literature.  J Nutr. 2001;  131 3095S-3108S
• 74 Miltyk W, Craciunescu C N, Fischer L, Jeffcoat R A, Koch M A, Lopaczynski W, Mahoney C, Jeffcoat R A, Crowell J, Paglieri J, Zeisel S H. Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer.  Am J Clin Nutr. 2003;  77 875-882
• 75 Sharma P, Wisniewski A, Braga-Basaria M, Xu X, Yep M, Denmeade S, Dobs A S, DeWeese T, Carducci M, Basaria S. Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy.  J Urol. 2009;  182 2265-2272
• 76 Spentzos D, Mantzoros C, Regan M M, Morrissey M E, Duggan S, Flickner-Garvey S, McCormick H, DeWolf W, Balk S, Bubley G J. Minimal effect of a low-fat/high soy diet for asymptomatic, hormonally naive prostate cancer patients.  Clin Cancer Res. 2003;  9 3282-3287
• 77 Joniau S, Goeman L, Roskams T, Lerut E, Oyen R, Van P H. Effect of nutritional supplement challenge in patients with isolated high-grade prostatic intraepithelial neoplasia.  Urology. 2007;  69 1102-1106
• 78 Kumar N B, Krischer J P, Allen K, Riccardi D, Besterman-Dahan K, Salup R, Kang L, Xu P, Pow-Sang J. A phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer.  Nutr Cancer. 2007;  59 163-168
• 79 Kumar N B, Krischer J P, Allen K, Riccardi D, Besterman-Dahan K, Salup R, Kang L, Xu P, Pow-Sang J. Safety of purified isoflavones in men with clinically localized prostate cancer.  Nutr Cancer. 2007;  59 169-175
• 80 Thompson L U, Chen J M, Li T, Strasser-Weippl K, Goss P E. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer.  Clin Cancer Res. 2005;  11 3828-3835
• 81 DiSilvestro R A, Goodman J, Dy E, Lavalle G. Soy isoflavone supplementation elevates erythrocyte superoxide dismutase, but not plasma ceruloplasmin in postmenopausal breast cancer survivors.  Breast Cancer Res Treat. 2005;  89 251-255
• 82 Mentor-Marcel R, Lamartiniere C A, Eltoum I A, Greenberg N M, Elgavish A. Dietary genistein improves survival and reduces expression of osteopontin in the prostate of transgenic mice with prostatic adenocarcinoma (TRAMP).  J Nutr. 2005;  135 989-995
• 83 Mentor-Marcel R, Lamartiniere C A, Eltoum I E, Greenberg N M, Elgavish A. Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP).  Cancer Res. 2001;  61 6777-6782
• 84 El Touny L H, Banerjee P P. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis.  Cancer Res. 2009;  69 3695-3703
• 85 Dai J, Li B, Shi J, Peng L, Zhang D, Qian W, Hou S, Zhao L, Gao J, Cao Z, Zhao J, Wang H, Guo Y. A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo.  Cancer Immunol Immunother. 2010;  59 355-366
• 86 Forootan S S, Foster C S, Aachi V R, Adamson J, Smith P H, Lin K, Ke Y. Prognostic significance of osteopontin expression in human prostate cancer.  Int J Cancer. 2006;  118 2255-2261
• 87 Fink B N, Steck S E, Wolff M S, Britton J A, Kabat G C, Gaudet M M, Abrahamson P E, Bell P, Schroeder J C, Teitelbaum S L, Neugut A I, Gammon M D. Dietary flavonoid intake and breast cancer survival among women on Long Island.  Cancer Epidemiol Biomarkers Prev. 2007;  16 2285-2292
• 88 Shu X O, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival.  JAMA. 2009;  302 2437-2443
• 89 Korde L A, Wu A H, Fears T, Nomura A M, West D W, Kolonel L N, Pike M C, Hoover R N, Ziegler R G. Childhood soy intake and breast cancer risk in Asian American women.  Cancer Epidemiol Biomarkers Prev. 2009;  18 1050-1059
• 90 Lee S A, Shu X O, Li H, Yang G, Cai H, Wen W, Ji B T, Gao J, Gao Y T, Zheng W. Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women's Health Study.  Am J Clin Nutr. 2009;  89 1920-1926