This section contains the following key information:
- Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
- Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.
- Genistein affects components of multiple growth and proliferation -related pathways in prostate cancer cells, including the COX-2 /prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.
- Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
- Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.
- Epidemiologic studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
- Limited human prevention studies have been conducted, and, so far, they have not yielded consistent or definitive findings.
- Treatment trials of various doses and preparations of soy isoflavones in men with prostate cancer have yielded varying results but have generally failed to demonstrate significant effects on prostate-specific antigen (PSA) levels.
- A few clinical trials of soy protein or whole soy products have provided preliminary evidence of the ability of these products to lower PSA levels in men with prostate cancer.
- Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.
General Information & History
Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.
Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity. Other isoflavones found in soy include daidzein and glycitein. Isoflavones help soybeans survive in times of stress and have antioxidant, antimicrobial, and antifungal properties.
Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours following soy product consumption. Isoflavones are phytoestrogens (they bind to estrogen receptors) with a greater binding affinity for estrogen receptor beta than for estrogen receptor alpha.
Some studies suggest that soy may have health benefits, including decreasing risk of cardiovascular disease and cancer. A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often overexpressed in cancer cells. Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation. In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.
In vitro studies
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation. In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin -8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties. Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro . However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.
Combinations of isoflavones
Some experiments have been conducted comparing effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one such study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggest that products containing a combination of active compounds (e.g., "whole foods") may be more effective in preventing cancer than individual compounds. Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.
At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.
Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects. In another study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer. In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment. In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/day) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.
Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/day), mixed isoflavones (50 mg/kg body weight/day; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.
Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from healthy control subjects to prostate cancer patients at various stages of the disease) and have used a number of different interventions such as soy supplements, beverages, and breads.
In 2009, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) may significantly decrease the risk of prostate cancer. No association was found between high consumption of fermented soy foods (e.g., miso) and prostate cancer risk. An updated 2013 meta-analysis confirmed the good safety profile of isoflavones but indicated no significant differences between treated and control groups for PSA levels or sex steroid endpoints (sex hormone-binding globulin, testosterone, free testosterone, estradiol and dihydrotestosterone). In another study, urinary concentrations of phytoestrogens were assessed in healthy Jamaican men and men newly diagnosed with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a metabolite of daidzein) were at a lower risk of prostate cancer than men who were nonproducers.
In one study, Japanese men who had undergone prostate biopsy, but who did not have cancer, were randomly assigned to receive a supplement containing soy isoflavones (40 mg; comprised of 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg) or a placebo for 6 months. Overall, there were no differences in PSA levels between the placebo and the treatment groups. However, when subjects were subdivided according to baseline PSA level, patients with a higher baseline PSA level (PSA ≥10 ng/mL) who received supplements exhibited statistically significantly larger decreases in PSA than did patients in the placebo group (P = .02).
Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a low soy (usual diet) or high-soy (two daily soy servings) diet for 3 months. Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet. These findings suggest that this type of soy intervention study is feasible (i.e., the participants complied with dietary instructions) and that soy may be a potential chemopreventive agent.
In another study, men at risk of prostate cancer or with low-grade prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate that results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/day for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/day for alcohol-washed soy protein (containing 57% genistein, 20% daidzein, and 23% glycitein), and 0 mg/day for milk protein. Soy protein consumption did not alter prostate tissue biomarkers, alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.
Other plants also contain some of the same isoflavones found in soy. In one study, patients with elevated PSA levels but negative prostate biopsy specimens received a daily isoflavone preparation extracted from red clover (60 mg/day; which contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. Following 12 months of treatment, there was a significant reduction in PSA levels (P = .019) and a nonsignificant decrease in prostate volume (P = .097). In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.
Treatment of prostate cancer
In a study reported in 2010, patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily (providing approximately 65-90 mg isoflavones) for 6 months. The results showed that the soy beverage was well-tolerated and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.
In one small (n = 20), open-label study, patients with rising PSA levels following previous therapy consumed soy milk three times a day (141 mg isoflavonoid/day) for 12 months. The results showed that drinking soy milk was associated with a greater than 50% decline in PSA level in one patient and decreases in the rate of rise in serum PSA in 14 patients.
In another study, prostate cancer patients received genistein-rich supplements (450 mg genistein/day, plus 450 mg other aglycone isoflavones/day) for 6 months. The majority of patients who were undergoing active surveillance exhibited either no rise in PSA level or a decline of less than 50%. In a similar study, prostate cancer patients undergoing active surveillance were randomly assigned to receive a placebo or an isoflavone supplement containing high doses of genistein and daidzein (450 mg genistein, 300 mg daidzein, and other isoflavones) for 6 months. Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.
In a study reported in 2011, prostate cancer patients scheduled for radical prostatectomy were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (P = .051). In addition, the genistein intervention resulted in significantly lower levels of total cholesterol compared with placebo treatment (P = .013). Another group, however, conducted a randomized placebo-controlled trial to examine the effect of soy isoflavone capsules (80 mg/day of total isoflavones) on localized prostate cancer in 86 men who took the capsules for up to 6 weeks before prostatectomy. Changes in serum-free and total testosterone, PSA, and total cholesterol were not different between the two groups. The investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls.
In a phase II, randomized, double-blind, placebo-controlled trial [33,34] of men with localized prostate cancer (Gleason score 2–6) who were administered isoflavones (80 mg/day) or a placebo, significant increases in plasma isoflavones (P ≤ .001) were observed from baseline to 4 and 12 weeks in the isoflavone-treated group compared with placebo. Although greater mean reduction of serum-free testosterone was observed in men in the isoflavone-treated group than in men in the placebo group, these changes were not statistically significant for this duration of intervention (P = 0.3). Increasing concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) in the isoflavone-treated group was inversely correlated with changes in serum PSA, compared with the placebo arm.
In another phase II, multidose, randomized placebo-controlled trial, 45 men with localized prostate cancer received supplements with either 40, 60, or 80 mg of purified isoflavones or no supplement from the time of biopsy to prostatectomy. Significant increases in plasma isoflavones were observed with all isoflavone doses, compared with placebo, and significant increases in serum total estradiol were observed in the 40 mg and 60 mg isoflavone-treated arms. However, significant increases in serum-free testosterone were observed in the 60 mg isoflavone-treated arm. Compared with the control group and other treatment arms, the 40 mg isoflavone-treated arm had the lowest percentage of cells expressing Ki-67, although this was not statistically significant for this sample size and duration of intervention. This study concluded that 40 mg of isoflavones may be the best dose to use in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogenesis.
In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (60 mg/day isoflavones) or a placebo daily for 12 weeks. Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant.
Whole soy products
Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo radical prostatectomy were randomly assigned to receive soy supplements (three 27.2 mg tablets/day; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was sixfold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially anticarcinogenic levels of isoflavones. In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + linseed; 117 mg/day isoflavones) or low levels of phytoestrogens (wheat bread) until surgery. Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression.
In another small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years. Clinical benefits (i.e., decreased, attenuated, or stabilized PSA) were observed in five of the ten participants, suggesting that soy products may have positive effects in some prostate cancer patients.
Management of hormone therapy side-effects
Androgen deprivation therapy is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, and changes in cognition. In one study, men undergoing androgen deprivation therapy were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; 160 mg/day isoflavones) for 12 weeks. The study results showed no improvement in side effects following isoflavone treatment compared with placebo treatment. In a 2 X 2 factorial design study that investigated soy protein powder and venlafaxine in 120 androgen-deprived men, neither proved effective alone or in combination in decreasing hot flashes, although the number of vasomotor symptoms decreased significantly in all four arms over the 12-week trial. Soy protein, but not venlafaxine, produced statistically significant improvements in emotional and functional subscales on quality-of-life instruments.
Effects on inflammatory parameters
In another study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/day total isoflavones and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).
Prostaglandins promote inflammation and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis. The findings of a study reported in 2009 suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement (providing 81.6 mg/day isoflavones) for at least 2 weeks before surgery. The results showed a significant decrease in COX-2 mRNA levels (P < .01) and significant increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with specimens from the placebo group.
Current Clinical Trials
General information about clinical trials is also available from the NCI Web site.
Overall, soy was well tolerated in clinical studies of prostate cancer patients.[24,26,28,30,36,39] The most commonly reported side effects were gastrointestinal symptoms.[27,29,30] In addition, one study reported that a participant withdrew due to insomnia.
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