A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen.

Tomato and soy products are hypothesized to reduce the risk of prostate cancer or enhance efficacy of therapy. A study was completed to determine if men with active prostate cancer will adhere to a dietary intervention rich in tomato products and a soy protein supplement men (n = 41) with recurrent, asymptomatic prostate cancer were randomized among 2 groups: Group A (n = 20) consumed tomato products (no soy) for Weeks 0 through 4, targeting a minimum of 25 mg of lycopene/day. Group B (n = 21) consumed soy (no tomatoes) for Weeks 0 through 4, providing 40 g of soy protein/day. For Weeks 4 through 8, all men consumed a combined tomato-rich diet and soy supplements. No grade II through IV toxicities were observed. During Weeks 0 through 4, mean daily lycopene intake for Group A was 43 mg (+/- 15 mg) and mean soy intake for Group B was 39 g (+/- 1 g), remaining similar during Weeks 4 through 8. Serum lycopene increased from 0.72 +/- 0.09 micromol/l to 1.21 +/- 0.10 micromol/l (P < 0.0001) and urinary isoflavone excretion increased from not detectable to 54.1 +/- 5.7 micromol/l (P < 0.05) with 8 wk of diet intervention. Serum prostate-specific antigen decreased between Weeks 0 and 8 for 14 / 41 men (34%). Mean serum vascular endothelial growth factor for the entire group was reduced from 87 to 51 ng/ml (P < 0.05) over 8 wk. In conclusion, prostate cancer patients will consume diets rich in tomato products and soy with excellent compliance and bioavailability of phytochemicals. Further studies combining tomato and soy foods to determine efficacy for prostate cancer prevention or management are encouraged.

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

BACKGROUND: Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. METHODS: We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. RESULTS: The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. CONCLUSIONS: In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of preventive strategies.

Tomato phytochemicals and prostate cancer risk.

Mounting evidence over the past decade suggests that the consumption of fresh and processed tomato products is associated with reduced risk of prostate cancer. The emerging hypothesis is that lycopene, the primary red carotenoid in tomatoes, may be the principle phytochemical responsible for this reduction in risk. A number of potential mechanisms by which lycopene may act have emerged, including serving as an important in vivo antioxidant, enhancing cell-to-cell communication via increasing gap junctions between cells, and modulating cell-cycle progression. Although the effect of lycopene is biologically relevant, the tomato is also an excellent source of nutrients, including folate, vitamin C, and various other carotenoids and phytochemicals, such as polyphenols, which also may be associated with lower cancer risk. Tomatoes also contain significant quantities of potassium, as well as some vitamin A and vitamin E. Our laboratory has been interested in identifying specific components or combination of components in tomatoes that are responsible for reducing prostate cancer risk. We carried out cell culture trials to evaluate the effects of tomato carotenoids and tomato polyphenols on growth of prostate cancer cells. We also evaluated the ability of freeze-dried whole-tomato powder or lycopene alone to reduce growth of prostate tumors in rats. This paper reviews the epidemiological evidence, evaluating the relationship between prostate cancer risk and tomato consumption, and presents experimental data from this and other laboratories that support the hypothesis that whole tomato and its phytochemical components reduce the risk of prostate cancer.

Dietary influences on endocrine-inflammatory interactions in prostate cancer development.

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The focus of this review is to define the relationship between hormonal (testosterone/estrogens) stimulation of chronic inflammation, generation of reactive oxygen species (ROS), and uncontrolled prostate cell proliferation, and review putative dietary chemoprevention strategies that focus on these processes. It has been proposed that elevated estrogen in men who already have high blood testosterone are at high risk for prostate cancer. We hypothesized that elevated estrogen, in the presence of testosterone, causes prolonged activation of a redox-sensitive transcription factor, nuclear factor kappa B (NF kappa B), that initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative and nitrative damage. The inflammatory cascade is proposed to link with uncontrolled proliferation through up-regulated Wnt signal and abnormal catenin accumulation in the prostate. Finally, a strategy that emphasizes a "whole food" based approach to cancer prevention by selecting food products that bear anti-inflammatory and anti-proliferative properties may be most promising as an effective dietary chemopreventive strategy.

[14C]-lycopene and [14C]-labeled polar products are differentially distributed in tissues of F344 rats prefed lycopene.

Epidemiologic evidence suggests a possible role for lycopene-rich foods in the prevention of prostate cancer and cardiovascular disease. Despite active research in disease reduction, there is a paucity of information on the absorption, biodistribution and metabolism of lycopene. The aim of this study was to evaluate the biodistribution of 14C-lycopene (specific activity, 1.83 microCi/mg) and 14C-labeled products after an oral dose of 22 microCi of 14C-lycopene in male rats that had been prefed a lycopene-containing diet (0.25 g lycopene/ kg diet) for 30 d. The percentage of 14C excreted in feces and urine over the 168 h was 68%. Quantitatively, serum 14C levels were maintained between 3 and 24 h then decreased at 72 h (P < 0.05). At all time points the majority of tissue 14C was in the liver (approximately 72%), although total hepatic 14C decreased after 24 h. In a comparison of the extrahepatic tissue at 168 h, the 14C was greatest in adipose tissue followed by spleen and then adrenal; approximately 80% of the 14C in the liver was in the cis and all-trans configuration at all time points. At 3 h, the 14C in seminal vesicles was primarily in the all-trans plus 5-cis forms (70%), but by 168 h, 55% of 14C was present as 14C-polar products. Despite the presence of unlabeled lycopene in the prostate, the primary 14C form was in 14C-polar products (67-92%), even at 3 h. The percentage and amount of 14C-polar products in the dorsolateral prostate lobe increased from 3 to 24 h and then reached a plateau. The data suggest that lycopene may be metabolized differently among tissues in rats prefed lycopene.

Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets.

BACKGROUND: Consumption of tomato products or lycopene and energy restriction have been hypothesized to reduce the risk of human prostate cancer. We investigated the effects of these dietary variables in a rat model of prostate carcinogenesis. METHODS: Male rats (n = 194) treated with N-methyl-N-nitrosourea and testosterone to induce prostate cancer were fed diets containing whole tomato powder (13 mg lycopene/kg diet), lycopene beadlets (161 mg lycopene/kg diet), or control beadlets. Rats in each group were randomly assigned to either ad libitum feeding or 20% diet restriction. Differences between Kaplan-Meier survival curves for diet composition or restriction were tested with the log-rank test. Cox proportional hazards models were developed to examine the combined effect of diet composition and restriction on survival. Statistical tests were two-sided. RESULTS: Risk of death with prostate cancer was lower for rats fed the tomato powder diet than for rats fed control beadlets (hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.59 to 0.93; P =.009). In contrast, prostate cancer-specific mortality of the control and lycopene-fed rats was similar (P =.63). The proportions of rats dying with prostate cancer in the control, lycopene, and tomato powder groups were 80% (95% CI = 68% to 89%), 72% (95% CI = 60% to 83%), and 62% (95% CI = 48% to 75%), respectively. Rats in the diet-restricted group experienced longer prostate cancer-free survival than rats in the ad libitum-fed group (HR = 0.68, 95% CI = 0.49 to 0.96; P =.029). The proportion of rats that developed prostate cancer was 79% (95% CI = 69% to 86%) for ad libitum-fed rats and 65% (95% CI = 54% to 74%) for rats fed restricted diets. No interactions were observed between diet composition and dietary restriction. CONCLUSIONS: Consumption of tomato powder but not lycopene inhibited prostate carcinogenesis, suggesting that tomato products contain compounds in addition to lycopene that modify prostate carcinogenesis. Diet restriction also reduced the risk of prostate cancer. Tomato phytochemicals and diet restriction may act by independent mechanisms.

Ultraviolet radiation modulates nuclear factor kappa B activation in human lens epithelial cells.

Exposure to ultraviolet radiation (UVR) is a known risk factor for cataract, but the molecular mechanisms involved have not been elucidated. We hypothesized that exposure to UVR would modulate the activation of nuclear factor kappa-B (NF-kappa B) within the human lens epithelium, since NF-kappa B is a key regulator of cellular responses to UVR stress in other cell types. Human lens epithelial (HLE) cells were exposed to acute physiological doses of ultraviolet A (UVAR), B (UVBR), C (UVCR) radiation, or interleukin-1 beta (IL-1 beta) and NF-kappa B activation was measured by electrophoretic shift assay (EMSA). Phosphorylation of I kappa B in response to UVAR was measured by Western blotting. Irradiation of HLE cells with UVAR (0-1100 J/m(2)) did not reduce cell survival, while UVBR (400-1600 J/m(2)) and UVCR (300-900 J/m(2)) significantly reduced HLE cell survival. EMSA analysis of HLE nuclear proteins indicated activation of NF-kappa B, but not activator protein-1 (AP-1), by UVAR. The effects of UVBR and UVCR were less pronounced. Exposure of HLE cells to UVAR (0-900 J/m(2)) followed by a 30-min incubation resulted in a dose-dependent activation of NF-kappa B. UVAR-induced NF-kappa B activation in HLE cells was evident 10 min postirradiation, maximal at 60 min and returned to control levels by 120 min. Western blot analysis of phosphorylation of the NF-kappa B inhibitory protein, I kappa B, revealed that UVAR activates NF-kappa B via a mechanism involving the phosphorylation of I kappa B-alpha; this effect was dose-dependent. Supershift analysis demonstrated that UVAR and IL-1 beta activate the transcriptionally active p65/p50 NF-kappa B dimer. These studies demonstrate that UVAR activates NF-kappa B in HLE cells in a time- and dose-dependent manner via signaling through I kappa B-alpha. The activation of NF-kappa B in HLE cells by UVAR may have implications for the development and progression of cataract and other related ocular disorders.

Bioavailability of all-trans and cis-isomers of lycopene.

Lycopene, the predominant carotenoid in tomatoes, is among the major carotenoids in serum and tissues of Americans. Although about 90% of the lycopene in dietary sources is found in the linear, all-trans conformation, human tissues contain mainly cis-isomers. Several research groups have suggested that cis-isomers of lycopene are better absorbed than the all-trans form because of the shorter length of the cis-isomer, the greater solubility of cis-isomers in mixed micelles, and/or as a result of the lower tendency of cis-isomers to aggregate. Work with ferrets, a species that absorbs carotenoids intact, has demonstrated that whereas a lycopene dose, stomach, and intestinal contents contained 6-18% cis-lycopene, the mesenteric lymph secretions contained 77%-cis isomers. The ferret studies support the hypotheses that cis-isomers are substantially more bioavailable then all-trans lycopene. In vitro studies suggest that cis-isomers are more soluble in bile acid micelles and may be preferentially incorporated into chylomicrons. The implications of these findings are not yet clear. Rats appear to accumulate lycopene in tissues within the ranges reported for humans, suggesting that they can be used to study effects of lycopene isomers on disease processes. Investigations are underway to determine whether there are biological differences between all-trans and various cis-isomers of lycopene regarding its antioxidant properties or other biological functions.

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats.

Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors vertical line 1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1-2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in human prostate carcinogenesis and represent potential biomarkers for the assessment of dietary, chemopreventive and therapeutic agents.