A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia.

A diverse body of evidence suggests that lycopene might inhibit prostate cancer development. We conducted a 6-mo repeat biopsy randomized trial among men with high-grade prostatic intraepithelial neoplasia (HGPIN). Here we report results for serum lycopene, prostate specific antigen (PSA) and insulin-like growth factor (IGF) proteins, histopathological review, and tissue markers for proliferation [minichromosome maintenance protein 2 (MCM-2)] and cell cycle inhibition (p27). Participants consumed placebo or tomato extract capsules containing 30 mg/day lycopene. Pre- and posttreatment biopsies were immunostained and digitally scored. Serum lycopene was determined by LC-MS-MS. In secondary analyses, pathologists blindly reviewed each biopsy to score histological features. Fifty-eight men completed the trial. Serum lycopene increased 0.55 µmol/L with treatment and declined 0.29 µmol/L with placebo. We observed no meaningful differences in PSA, IGF-1, or IGF binding protein 3 concentrations between groups, nor any differences in expression of MCM-2 or p27 in epithelial nuclei. Prevalences of cancer, HGPIN, atrophy, or inflammation posttreatment were similar; however, more extensive atrophy and less extensive HGPIN was more common in the lycopene group. Despite large differences in serum lycopene following intervention, no treatment effects were apparent on either the serum or benign tissue endpoints. Larger studies are warranted to determine whether changes observed in extent of HGPIN and focal atrophy can be replicated.

Death receptor 5 expression is inversely correlated with prostate cancer progression.

Prostate carcinoma (PCa) is one of the most common cancers in men. Prostate-specific antigen (PSA) has been widely used to predict the outcome of PCa and screening with PSA has resulted in a decline in mortality. However, PSA is not an optimal prognostic tool as its sensitivity may be too low to reduce morbidity and mortality. Consequently, there is a demand for additional robust biomarkers for prostate cancer. Death receptor 5 (DR5) has been implicated in the prognosis of several cancers and it has been previously shown that it is negatively regulated by Yin Yang 1 (YY1) in prostate cancer cell lines. The present study investigated the clinical significance of DR5 expression in a prostate cancer patient cohort and its correlation with YY1 expression. Immunohistochemical analysis of protein expression distribution was performed using tissue microarray constructs from 54 primary PCa and 39 prostatic intraepithelial neoplasia (PIN) specimens. DR5 expression was dramatically reduced as a function of higher tumor grade. By contrast, YY1 expression was elevated in PCa tumors as compared with that in PIN, and was increased with higher tumor grade. DR5 had an inverse correlation with YY1 expression. Bioinformatic analyses corroborated these data. The present findings suggested that DR5 and YY1 expression levels may serve as progression biomarkers for prostate cancer.

Association of Pb, Cd, and Se concentrations and oxidative damage-related markers in different grades of prostate carcinoma.

Prostate cancer is known to be affected by the heavy metal levels and oxidative damage of the body, yet there are very few studies which look into the way it occurs. The aim of this study was to determine whether blood and tissue lead (Pb), cadmium (Cd), and selenium (Se) levels are associated with oxidative damage in the context of prostate cancer progression and development. Seventy-nine patients comprising 25 patients with benign prostatic hypertrophy (BPH), 23 patients with malignant prostatic carcinoma (malign Ca), 16 patients with low-grade prostatic intraepithelial neoplasia (LGPIN), and 15 patients with high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosed on the basis of their clinical profile, transrectal ultrasonography, and histopathology were included in this study. Cd and Pb levels in whole blood were found to be increased in patients with HGPIN compared with the BPH group; also, the levels of Cd in whole blood and tissue were found to be increasing in patients with malign Ca, unlike BPH patients. Moreover, the levels of malondialdehyde (MDA) in plasma and tissue were significantly increased in malign Ca, LGPIN, and HGPIN than those in BPH. However, the levels of tissue Pb were found to be decreasing in BPH, unlike the malign Ca and HGPIN patients, and the levels of tissue protein carbonyls in malign Ca were significantly lower than those in HGPIN. The levels of tissue reduced glutathione (GSH) in malign Ca were significantly lower than those in BPH. Additionally, the levels of Se in serum and tissue in LGPIN were significantly lower than those in BPH. The serum Se levels in HGPIN were also significantly lower than those in BPH and malign Ca groups. Furthermore, the concentrations of serum Se in LGPIN were significantly lower than those in malign Ca. From the Pearson correlation analysis, there were significant positive correlations between tissue Cd and MDA levels in malign Ca, LGPIN, and HGPIN and between the tissue Pb and tissue MDA and protein carbonyl levels in malign Ca. Blood Pb and tissue Pb were also significantly positively correlated with plasma MDA and protein carbonyl levels in malign Ca. In addition, blood Pb was significantly positively correlated with tissue MDA and protein carbonyl levels in malign Ca, and a significant positive correlation was also found between blood Cd and plasma protein carbonyls and tissue MDA in LGPIN. We observed that altered prooxidant-antioxidant balance and heavy metal levels may lead to an increase in oxidative damage and may consequently play an important role in prostate carcinogenesis. These findings indicate that changes in the levels of Pb, Cd, Se, MDA, protein carbonyls, and GSH in the blood and/or tissue are related to the prostatic carcinoma development and progression, although triggering one of the mentioned changes is unknown; therefore, further study is required to determine the exact steps of the process and clarify the roles of different substances in order to obtain a more detailed explanation of the phenomenon.

Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model.

Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment and prevention are necessary for inhibiting disease progression to a hormone refractory state. One of the approaches to control prostate cancer is prevention through diet, which inhibits one or more neoplastic events and reduces the cancer risk. For centuries, Ayurveda has recommended the use of bitter melon (Momordica charantia) as a functional food to prevent and treat human health related issues. In this study, we have initially used human prostate cancer cells, PC3 and LNCaP, as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. We observed that prostate cancer cells treated with BME accumulate during the S phase of the cell cycle and modulate cyclin D1, cyclin E, and p21 expression. Treatment of prostate cancer cells with BME enhanced Bax expression and induced PARP cleavage. Oral gavage of BME, as a dietary compound, delayed the progression to high-grade prostatic intraepithelial neoplasia in TRAMP (transgenic adenocarcinoma of mouse prostate) mice (31%). Prostate tissue from BME-fed mice displayed approximately 51% reduction of proliferating cell nuclear antigen expression. Together, our results suggest for the first time that oral administration of BME inhibits prostate cancer progression in TRAMP mice by interfering cell-cycle progression and proliferation.

1,4-phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells.

The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and phosphatidylinositol 3-kinase/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone-refractory prostate disease. Our initial investigations show that the naturally occurring organoselenium compound selenomethionine (SM) and the synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) can inhibit human prostate cancer cell viability; however, in contrast to SM, p-XSC is active at physiologically relevant doses. In the current investigation, we show that p-XSC, but not an equivalent dose of SM, alters molecular targets and induces apoptosis in androgen-responsive LNCaP and androgen-independent LNCaP C4-2 human prostate cancer cells. p-XSC effectively inhibits AR expression and transcriptional activity in both cell lines. p-XSC also decreases Akt phosphorylation as well as Akt-specific phosphorylation of the AR. Inhibition of Akt, however, does not fully attenuate p-XSC-mediated downregulation of AR activity, suggesting that inhibition of AR signaling by p-XSC does not occur solely through alterations in the phosphatidylinositol 3-kinase/Akt survival pathway. Our data suggest that p-XSC inhibits multiple signaling pathways in prostate cancer, likely accounting for the downstream effects on proliferation and apoptosis.

High-dose dietary zinc promotes prostate intraepithelial neoplasia in a murine tumor induction model.

To evaluate the role of high-dose dietary zinc in the process of prostate malignancy, 60 Sprague-Dawley rats were randomly divided into four groups: tumor induction with carcinogen and hormone (group 1), oral zinc administration without tumor induction (group 2), oral zinc administration with tumor induction (group 3) and a control without zinc administration or tumor induction (group 4). Zinc was supplied orally in the form of zinc sulfate heptahydrate dissolved in drinking water to groups 2 and 3 for 20 weeks. Although the serum level of zinc measured at 20 weeks was maintained similarly in each group (P = 0.082), intraprostatic zinc concentrations were statistically different. Group 1 prostates contained the least amount of zinc in both the dorsolateral and ventral lobes at levels of 36.3 and 4.8 microg g(-1), respectively. However, in group 3, zinc levels increased in both lobes to 59.3 and 12.1 microg g(-1), respectively, comparable with that of group 4 (54.5 +/- 14.6 and 14.1 +/- 2.4 microg g(-1)). In spite of these increases in zinc concentration, the prevalence of prostate intraepithelial neoplasm was rather increased in group 3 (53.3% and 46.7%) compared with group 1 (33.3% and 33.3%) in both dorsolateral and ventral prostate lobes. Although prostate intraepithelial neoplasm did not develop in any prostate in group 4, zinc administration did induce prostate intraepithelial neoplasm in group 2 (46.7% and 40.0%). Thus, although high dietary zinc increased intraprostatic zinc concentrations, it promoted, instead of preventing, prostate intraepithelial neoplasm in a murine prostate malignancy induction model.

Adenocarcina of the mouse prostate growth inhibition by celecoxib: downregulation of transcription factors involved in COX-2 inhibition.

BACKGROUND: Epidemiological studies have shown a decreased risk of prostate cancer among men who regularly take aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we examined a dose-dependent effect of a cyclooxygenase-2 (COX-2) inhibitor, celecoxib against transgenic adenocarcinoma of the mouse prostate. METHODS: Efficacy of four different doses in parts per million of celecoxib, such as 200 ppm, 400 ppm, 600 ppm, and 1,000 ppm representing very low, moderate, and high doses, respectively were tested against adenocarcinoma of the mouse prostate using a transgenic adenocarcinoma of the mouse prostate (TRAMP) model assay. RESULTS: Dietary supplement of celecoxib at doses of 400 ppm, 600 ppm, and 1,000 ppm are most effective against mPIN (mouse prostatic intraepithelial neoplasia) and adenocarcinoma of the prostate. Tumor growth inhibition by celecoxib was associated with increased rate of apoptosis. At 1,000 ppm, a complete inhibition of the PIN lesions was extended to limit the growth of adenocarcinoma (from 85% to 15%) and metastasis of the mouse prostate. The chemopreventive effect was significant (P<0.01) at 400 ppm, 600 ppm, and 1,000 ppm doses compared to that at the lowest dose of 200 ppm and control. A dose-dependent effect on tumor growth inhibition was associated with reduced expression of NF-kappaBp65 and COX-2. CONCLUSIONS: Dietary supplementation of celecoxib at different doses provides evidence for the suppression of prostate adenocarcinoma tumor growth in a dose-dependent manner. Suppression of adenocarcinoma by celecoxib further limits the growth of metastatic prostate cancer.

Loss of stearoyl-CoA desaturase expression is a frequent event in prostate carcinoma.

Prostate carcinogenesis is influenced by genetic alterations resulting in a biochemical condition that favors cell proliferation and survival. Studies of prostate carcinoma using comparative genomic hybridization and cDNA microarray analysis indicate that numerous biochemical processes may be affected during cellular transformation and progression to an invasive phenotype. Among the consistently observed tumor-associated changes are alterations in fatty acid metabolism that influence diverse cellular activities such as signaling, energy utilization, and membrane fluidity. Increases in fatty acid synthase (FAS) levels have been shown to be one of the earliest and most frequent molecular alterations in prostate carcinogenesis. We sought to identify tumor-associated changes in the expression of genes with functional roles associated with lipid metabolism. Defined populations of normal and neoplastic prostate epithelium were acquired by laser capture microdissection and transcript levels were measured by cDNA microarray hybridization. We determined that stearoyl-CoA desaturase (SCD) transcripts were downregulated in cancer relative to normal epithelium. These results were confirmed by quantitative PCR. Further analysis by immunohistochemical evaluation of radical prostatectomy samples employed a quantitative scoring system with a range of 0-300. The median SCD expression levels were 150, 45 and 10 for normal, PIN and carcinoma samples, respectively. Statistically significant differential SCD expression between normal and cancerous epithelium was determined at the p=0.001 level, and between PIN and prostate carcinoma at the p=0.03 level. Of these cases, 92% overexpressed fatty acid synthase (FAS) in cancerous cells and 84.7% exhibited the signature of FAS overexpression and SCD loss in prostate carcinoma as compared to normal prostate epithelium. These results indicate that loss of SCD expression is a frequent event in prostate adenocarcinoma, and further supports a role for altered lipid metabolism as a factor in the process of carcinogenesis.