Dietary habits and incidence of prostate cancer (PCa) are very different in several parts of the world. Among the differences between Eastern and Western diets is the greater intake of soy in the Eastern cultures. This might be one factor contributing to a lower incidence of PCa in Asian men. Many studies using PCa cells and animal studies of chemical carcinogenesis have shown that a wide range of dietary compounds have cancer chemopreventive potential. Therefore, the interest in nutrition-based approaches for prevention and treatment of PCa is increasing. We reviewed all experimental preclinical in vitro and in vivo data as well as clinical trials performed with soy isoflavone genistein for prevention and treatment of PCa. The preclinical data for genistein presented in this review show a remarkable efficacy against PCa cells in vitro with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, seemingly well-conducted animal experiments support the belief that genistein might have a clinical activity in human cancer therapy. However, it is difficult to make definite statements or conclusions on clinical efficacy of genistein because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardized drug formulation. Although some results from these genistein studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. The presented data potentially allow recommending patients the use of genistein as in soy products in a preventive setting. However, at present there is no convincing clinical proof or evidence that genistein might be useful in PCa therapy.
Dietary habits and prostate cancer (PCa) incidence are very different in several parts of the world. For example, the incidence of PCa is very low in most of Asia (as low as 1.0 per 100 000 men). The reason believed for this phenomenon is low animal fat intake together with a diet rich in fiber and soy.1 In contrast, high-fat consumption and a low-phytochemical diet are very common in Western countries, with higher incidences of PCa (up to >100 per 100 000 men).2, 3 Although there might be some problematic aspects with cancer registries in Far East countries, there is an additional evidence for the role of diet in migration studies. It has been shown that individuals with the same genetic background (for example, Japanese men migrated to the United States) have a risk of PCa comparable to the incidence of PCa of the country they live in.4 However, epidemiological studies that investigate the relation between the intake of fruits and vegetables and the risk of PCa balance between promising or disillusioning results. Many confounding factors present in clinical studies make assessment and interpretation of the effects of diet on cancer risk difficult. These difficulties are evident in a large study on food consumption and cancer incidence in Europe, the European Prospective Investigation into Cancer and Nutrition, where no association was observed between vegetable and fruit intake and the risk of PCa.5, 6 Therefore, the large geographical differences observed are probably not only due to genetic dispositions but relate to complex environmental and sociocultural (nutrition) factors.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27
In principle, PCa represents an ideal target for nutritional prevention due to its long latency, its high incidence, tumor marker availability (prostate-specific antigen, PSA) and identifiable preneoplastic lesions and risk groups. The interest in nutrition-based approaches for prevention and treatment of PCa is increasing. However, the interest is most evident in patients already suffering from the disease. Patients use increasingly complementary and alternative medicines (CAMs) for several reasons: first, in the hope to support the immune system to fight the cancer in addition to conventional treatment. Second, in the hope to minimize morbidity associated with conventional treatment and third in fear of suffering and dying from PCa in the case conventional treatment fails.28 CAM is a widely used term comprising techniques, methods, herbal medicines and nutrition supplements used in addition to mainstream care for symptom management and improving quality of life in cancer patients. Many of these alternative therapies comprise unproven methods promoted as treatment or cure with questionable benefit. On the other side, there is increasing evidence in the current scientific medical literature on an effectively delivered activity of phytotherapeutics in modulating cancer cell growth. Phytochemicals differ from what are traditionally termed nutrients because they are not a necessity for normal metabolism nor will their absence result in a deficiency disease. Many studies using PCa cells and animal studies of chemical carcinogenesis have shown that a wide range of dietary compounds have cancer chemopreventive potential. This paper critically assesses the preclinical and clinical data on one of the most popular phytosubstances, the soy flavonoid genistein when used in PCa prevention and treatment.
Phytoestrogens are naturally occurring phenolic plant compounds classified as flavones, isoflavones, coumestans and lignans. They are highly concentrated in soy products (beans, tofu) and plant lignans are found in legumes, whole grain, and various seeds and vegetables.8, 29 Biochemically, phytoestrogens are heterocyclic phenols with a structural similarity to estrogenic steroids (mammalian endogenous estrogens) and therefore, these compounds display estrogen-like activity or weak antiestrogen-like properties.29, 30 The beneficial effects of a soy diet have been attributed to isoflavones. Genistein, the predominant isoflavone in human nutrition is derived mainly from soybeans but also from other legumes, including peas, lentils or beans. Quercetin is the main representative of the flavonol class and a polyphenolic antioxidant found in a variety of fruits and vegetables. It is highly concentrated in onions, broccoli, apples, grapes (red wine) and in soybeans, and is also a component of gingko biloba.
In vitro effects of phytoestrogens
Physiological concentrations of the soy-derived isoflavone genistein were shown to downregulate the androgen receptor of PCa cells via the estrogen receptor β, resulting in a modified response to hormonal stimuli.31 They also inhibit several steroid-metabolizing enzymes such as 5-α-reductase or aromatase.32, 33 It has been postulated that these activities may be protective for PCa by creating a more favorable hormonal milieu. Isoflavones have been well analyzed in human PCa cells over the past years. Genistein inhibited the growth and induced apoptosis in LNCaP, DU-145 and PC3 prostatic cancer cells in a concentration 20 μM.34, 35, 36, 37, 38, 39, 40, 41, 42 Genistein blocked the cell cycle progression at G1, inhibited PSA expression and modulated cell cycle gene regulation.37, 38, 40, 43 Expression of telomerase reverse transcriptase, c-myc mRNA and the MDM2 oncogene were downregulated by genistein, whereas p21 mRNA increased in response to genistein in PCa cells DU-145 and LNCaP.42, 44 In another study, genistein inhibited endothelial cell proliferation and in vitro angiogenesis associated with cancer progression at concentrations of 5 and 150 μM.45 Further, it was demonstrated that genistein interfered with apoptosis signal transduction by downregulating Bcl-XL expression.46 Genistein inhibited the nuclear factor-κB (NF-κB) activation via the AKT signaling pathway and induced apoptosis in androgen-sensitive PCa cell line LNCaP and the androgen-insensitive cell line PC3 in a concentration of 50 μM, whereas no apoptosis was seen in nontumorigenic CRL-2221 human prostate epithelial cells under genistein treatment.41, 47 The AKT signaling pathway is an important survival pathway in cellular transduction activated by various growth factors like the epidermal growth factor. AKT also regulates the NF-κB activation. NF-κB activity was completely abrogated in cells pretreated with genistein.41, 43, 47, 48 Furthermore, the effects of genistein on PC3 cancer cells and experimental PC3 bone tumors were evaluated by injecting these cells into human bone fragments previously implanted in immunodeficient (severe combined immunodeficiency, SCID) mice. Genistein significantly inhibited PC3 bone tumor growth by regulating the expression of multiple genes involved in the control of cell growth, apoptosis and metastasis both in vitro and in vivo. For example, the expression of various metalloproteinases (MMPs) in PC3 bone tumors was inhibited by genistein treatment, whereas osteoprotegerin was upregulated. MMP immunostaining and transfection experiments also demonstrated inhibition of MMP-9 expression in PC3 cells in vitro and PC3 bone tumors in vivo after genistein treatment.49
In vivo effects of phytoestrogens
A study with Lobund–Wistar rats that received a high-isoflavone diet showed a significant reduction of prostate tumor growth compared to the control group receiving a low-isoflavone diet.50 Another study with TRAMP mice fed on a genistein-rich diet also found reduction of tumor incidence.51 Additionally, genistein lowered androgen and estrogen-receptor expression in the rat prostate, shown by a study of a diet with 250–1000 mg genistein per kg fed to male Sprague–Dawley rats.52, 53 These, and other trials with animal models provide promising data for treatment of PCa with isoflavonoids.54, 55, 56, 57 A compilation of the preclinical in vitro and in vivo data is shown in Table 1.
Clinical data on genistein
Although there are plenty of experimental data available, large epidemiological trials to underline the antitumoral effect of isoflavones are rare. The first prospective cohort study was conducted in 1994 and showed that flavonoid intake was not associated with mortality from cancer.16 This was confirmed in a cross-national study of seven countries with 16 cohorts. A positive effect on coronary heart disease might be attributed to flavonoid intake but not cancer mortality.60 However, another cross-national study from 42 countries found that soy products were significantly protective on PCa mortality (P=0.0001) with an effect size per kilocalorie at least four times as large as that of any other dietary factor.61 A substantial review of studies that have assessed the direct relation between the individual dietary intake of soy products and the risk of PCa was done by Ganry in 2005. Ganry analyzed epidemiological studies providing data on (1) dietary soy intake or flavonoids intake, (2) urinary excretion of isoflavones or lignans or (3) blood measurements of isoflavones or lignans. Soy was used as a marker for isoflavone intake. Overall, the results of these studies did not show protective effects. Only four of these studies were prospective, and none of them found statistically significant PCa reductions.11
However, there are some phase I and II trials evaluating efficacy and safety of genistein in patients with PCa. In a nonrandomized, nonblinded trial of 38 patients (20 with clinically significant PCa and 18 controls), a daily intake of 160 mg isoflavones extract until radical prostatectomy led to significantly higher apoptosis of tumor cells (P=0.0018). No adverse events were reported, the median treatment time was 20 days.62 With the objective to assess the potential genotoxicity of a purified unconjugated isoflavone mix, Miltyk et al.63 observed 20 PCa patients treated with 300 mg genistein per day for 28 days and with 600 mg per day for 56 days but could not find any significant genetic damage. A study by De Vere White et al.64 tried to determine whether supplemental amounts of soy isoflavone (genistein-rich extract) would lower PSA levels more than 50% in patients with PCa. A total of 62 men with histologically proven PCa who had two consecutive elevated PSA readings were accrued into an open-label pilot study. Patients took capsules containing the genistein-rich extract three times daily by mouth. The subjects were in one of five groups: after radical retropubic prostatectomy (n=9), after radiotherapy (n=17), after both radical retropubic prostatectomy and radiotherapy (n=6), off-cycle during hormonal therapy (intermittent hormones; n=14) or active surveillance (n=16). The primary end point for the trial was a 50% reduction in the PSA level at 6 months compared with before treatment. Fifty-two patients were available for evaluation at 6 months. One of 52 patients had a more than 50% reduction in the PSA level, additional 7 patients had PSA reductions that were less than 50%. All eight patients with lower PSA levels at 6 months were in the active surveillance (watchful waiting) treatment subgroup. Repeated measure regression models allowing for correlation between initial levels and change also indicated a decline in PSA in this group compared with other groups: 0 of 52 had a complete response, 9 (17%) had a partial response, 8 (15%) had stable disease and 35 (67%) had disease progression. Taken together, genistein may hold some promise in PCa treatment but more study is warranted.64 A summary of clinical trails with genistein is depicted in Table 2.
To establish the influence of a nutritional compound as genistein on cancer genesis, promotion or progression carefully designed, larger-scale, prospective randomized trials should further support the epidemiological and experimental data. Numerous case–control studies, but unfortunately only a few prospective randomized clinical trials have analyzed the influence of diet on PCa. Evidence-based data are needed to definitively prove the efficacy of genistein or other phytochemicals for PCa because of the growing interest in and use of herbal remedies as a persistent trend of our present-day health care. The summary of preclinical data for genistein presented in this review shows a remarkable efficacy against PCa cells in vitro with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, well-conducted animal experiments support the belief that genistein might have a clinical activity in human cancer therapy. However, the protocols chosen for the clinical phase I and II trials make interpretation of data quite difficult. Dose and concentrations of the drug/substance used in the studies were empirically derived and the manufacturing and preparation of the product was not standardized. Some analysis combined patients without stratification on androgen-dependent and androgen-independent tumors; some had small patient numbers, short treatment duration (<6 months) or did not have sufficient statistical power. It is difficult to make definite statements or conclusions because of the great variability and differences of the study results. Although some results from clinical genistein studies seem encouraging, reliable data on tumor recurrence, disease progression and survival are unknown. A major setback remains the problematic design and definition of end point criteria assessing the value of genistein in cancer therapy. The presented data potentially allow recommending patients in favor of the use of genistein with the intention to prevent against development of PCa. At this stage, there is not enough clinical evidence by clinical trials that genistein has an effect in the treatment of PCa.