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May 2006

Molecular effects of the isoflavonoid genistein in prostate cancer.

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

Clin Prostate Cancer. 2005 Sep;4(2):124-9

Soy isoflavone supplementation elevates erythrocyte superoxide dismutase, but not plasma ceruloplasmin in postmenopausal breast cancer survivors.

Soy isoflavone antioxidant effects may help prevent breast cancer re-occurrence, but isoflavone estrogen-like actions may increase breast cancer risk. These isoflavone actions can be reflected by effects on two copper enzymes activities, superoxide dismutase 1 (SOD 1), which has antioxidant function relevant to breast cancer prevention, and ceruloplasmin, which has its synthesis up-regulated by estrogen, and for which high values are associated with high breast cancer risk. A soy isoflavone-rich concentrate supplement was examined for effects on these two copper enzyme activities in post-menopausal breast cancer survivors (n = 7) in a crossover design with a placebo (24 days on supplement or placebo; 14 day wash out). The soy concentrate, but not the placebo, increased erythrocyte SOD 1 activities, but not ceruloplasmin activities or protein. The effect on superoxide dismutase activities was not likely due to increased copper intake since analysis of the soy extract showed little copper. The effect on superoxide dismutase was not accompanied by a change in urinary contents of 8-deoxyhydroxyguanosine, a DNA oxidant product, though perhaps this would change with a longer intervention. In summary, in regard to two copper enzyme activities, an isoflavone-rich soy concentrate showed an antioxidant effect considered relevant to breast cancer, but not an effect associated with estrogenic activity and increased breast cancer risk.

Breast Cancer Res Treat. 2005 Feb;89(3):251-5

Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay.

Anti-angiogenic strategies are emerging as an important tool for the treatment of cancer and inflammatory diseases. In the present investigation we isolated several isoflavones from a tempeh (fermented soyabean) extract. The isolated isoflavones were identified as 5,7,4’-trihydroxyisoflavone (genistein), 7,4’-dihydroxyisoflavone (daidzein), 6,7,4’-trihydroxyisoflavone (factor 2), 7,8,4’-trihydroxyisoflavone (7,8,4’-TriOH) and 5,7,3’,4’-tetrahydroxyisoflavone (orobol). The effects on angiogenesis of these isoflavones were evaluated in the chicken chorioallantoic membrane assay; their capacity to inhibit vascular endothelial growth factor-induced endothelial cell proliferation and expression of the Ets 1 transcription factor, known to be implicated in the regulation of new blood vessel formation, were also investigated. We found that all isoflavones inhibited angiogenesis, albeit with different potencies. Compared with negative controls, which slightly inhibited in vivo angiogenesis by 6.30%, genistein reduced angiogenesis by 75.09%, followed by orobol (67.96%), factor 2 (56.77%), daidzein (48.98%) and 7,8,4’-TriOH (24.42%). These compounds also inhibited endothelial cell proliferation, with orobol causing the greatest inhibition at lower concentrations. The isoflavones also inhibited Ets 1 expression, providing some insight into the molecular mechanisms of their action. Furthermore, the chemical structure of the different isoflavones suggests a structure-activity relationship. Our present findings suggest that the new isoflavones might be added to the list of low molecular mass therapeutic agents for the inhibition of angiogenesis.

Br J Nutr. 2005 Mar;93(3):317-23

The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN.

The isoflavone genistein (GEN), a biologically active component of soy foods, is associated with reduced breast cancer risk in women who consume soy-rich diets. GEN has been reported to influence many biological processes, of which suppression of cell proliferation and stimulation of apoptosis are considered to be the major pathways underlying its inhibition of tumorigenesis. This study evaluated the mechanism by which diets containing GEN promote mammary epithelial cell death. We report that mammary glands of young adult female rats exposed from gestation day 4 to postnatal day 50, to AIN-93G diets containing as sole protein source, casein (CAS) supplemented with GEN, or soy protein isolate (SPI+) had increased apoptosis, relative to rats fed CAS diet devoid of GEN. Mammary gland proliferation was unaffected by diet. The increased apoptotic index in mammary glands of GEN and SPI+ rats was accompanied by increased levels of the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome ten), albeit enhanced mammary expression of the pro-apoptotic p21, Bax and Bok genes was observed only in GEN-fed rats. GEN-induced apoptosis in MCF-7 cells was concomitant with increased PTEN expression, and this was abrogated by PTEN siRNA. MCF-7 cells treated with serum from GEN- or SPI(+)-fed rats had increased apoptosis as well as increased levels of the PTEN transcript. PTEN siRNA attenuated the increased apoptotic response of MCF-7 cells to serum from rats fed SPI+ or GEN, although the inhibition to basal (CAS serum) apoptotic levels was achieved only for cells treated with GEN serum. Decreased p21 and Bok gene expression accompanied the inhibition of apoptosis by PTEN siRNA. Data implicate PTEN in the induction of apoptosis by GEN and suggest that the promotion of apoptosis leading to inhibition of tumorigenesis in vivo by diets containing GEN may also involve the distinct activities of yet unknown GEN metabolite(s) and/or other systemic factors induced by GEN.

Carcinogenesis. 2005 Oct;26(10):1793-803

Impact of diet on prostate cancer: a review.

Epidemiological studies suggest that environmental factors may mediate the transformation of latent prostate cancer into clinically apparent tumors and that diet appears to influence this progression. Close correlations between average per capita fat intake and prostate cancer mortality internationally generated interest in underlying mechanisms for this link, such as through serum levels of androgens, free radicals, proinflammatory fatty acid metabolites, or insulin-like growth factor. Much interest currently lies in the potential of HMG-CoA reductase inhibitors (statins) to play a chemopreventative role in prostate cancer. Lycopene, a potent antioxidant found in tomatoes, may exert a protective effect in the prostate. Selenium and vitamin E have also been shown to decrease the risk of prostate cancer in some men. Calcium may support vitamin D-related antiproliferative effects in prostate cancer. Certain soy proteins, common in the Asian diet, have been shown to inhibit prostate cancer cell growth. Finally, green tea may also have a chemopreventive effect by inducing apoptosis. Despite confounding factors present in clinical studies assessing the effect of diet on cancer risk, the data remain compelling that a variety of nutrients may prevent the development and progression of prostate cancer.

Prostate Cancer Prostatic Dis. 2005;8(4):304-10

Meta-analysis of soy food and risk of prostate cancer in men.

There has been considerable interest in recent years in the role of soy in cancer etiology. The purpose of this meta-analysis was to evaluate epidemiologic studies available to date that related soy consumption to the risk of prostate cancer in men. We conducted a thorough Medline search for English-language publications, supplemented with hand-searching of articles’ bibliographies and nonindexed medical and professional journals, on epidemiologic studies of soy and prostate cancer. We identified 2 cohort and 6 case-control studies that met the following criteria for meta-analysis: a study must have assessed soy as a food and provided a risk estimate (relative risk or odds ratio) and its 95% confidence interval. Data from the same study population appearing in different journals were only used once with the most recent publication chosen for the analysis. Studies on fermented soy food were not included. We conducted the meta-analysis using a random-effects model. An analysis of these studies yielded an overall risk estimate of 0.70 (95% CI = 0.59-0.83; p < 0.001). No publication bias was detected. In summary, results of the analysis showed that consumption of soy food was associated with a lower risk of prostate cancer in men.

Int J Cancer. 2005 Nov 20;117(4):667-9

Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement.

OBJECTIVES: Epidemiological studies have shown significant relationships between the use of dietary components and prostate cancer incidence and mortality. Large studies of primary prevention, which confirm these findings, are desirable but costly and difficult to design. The present tertiary prevention study reports on the effect of a dietary supplement in comparison with placebo on the rate of increase of prostate-specific antigen (PSA). METHODS: 49 patients with a history of prostate cancer and rising PSA levels after radical prostatectomy (n = 34) or radiotherapy (n = 15) participated in a randomised, double-blind, placebo-controlled crossover study of a dietary supplement. Ethical approval of the protocol was obtained. Treatment periods of 10 weeks were separated by a 4-week washout period. The supplement consisted of soy, isoflavones, lycopene, silymarin and antioxidants as main ingredients. Changes in the rate of increase of PSA (PSA slope and doubling time) were the primary parameters of efficacy. Analyses according to intention to treat (ITT) and per protocol (PP) were carried out. RESULTS: Baseline parameters did not differ between randomised groups. Five participants were lost to follow-up, however 46 could be evaluated in an ITT analysis. PP analysis could be performed in 42 men with at least 5 PSA measurements. Per protocol analysis showed a significant decrease in PSA slope (p = 0.030) and (2)log PSA slope (p = 0.041). This translates into a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods. No treatment-based changes in safety parameters were observed during the study. CONCLUSIONS: The soy-based dietary supplement utilised in this study was shown to delay PSA progression after potentially curative treatment in a significant fashion. More extensive studies of the supplement may be indicated.

Eur Urol. 2005 Dec;48(6):922-30.