Prostate Cancer Chemoprevention Research Articles

Abstract 5253: Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state

Abstract Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa which is an herb widely used in traditional Chinese medicine to treat inflammation related diseases. We previously demonstrated that arctigenin strongly inhibited prostate tumor cell growth in cell culture and mouse models in non-obese state. The present study investigated the tumor inhibitory effect of arctigenin in obese state. An in vitro obese setting was created by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LAPC-4 and LNCaP prostate cancer cells. An ELISA analysis of 3T3-L1 conditioned medium revealed that three cytokines/growth factors were prominently secreted by 3T3-L1 cells, including IGF-1, VEGF, and MCP-1, and the sensitivity of prostate cancer cells to arctigenin was decreased in the obese state. However, arctigenin at a moderate concentration (10 µM) significantly inhibited the proliferation of both LAPC-4 and LNCaP cell by 40-50% at 96h in the co-culture system. Male severe combined immunodeficiency (SCID) mice was implanted subcutaneously with LAPC-4 xenograft tumors to confirm the tumor-inhibitory effect of arctigenin in vivo. Mice were fed high-fat diet containing 45% energy from fat, and treated with arctigenin at 50mg/kg b.w. orally or vehicle control for 6 weeks (n=10 per group). The tumor growth in arctigenin group was significantly inhibited by 40% compared to control, along with decreased blood concentrations of several cytokines including IGF-1, VEGF, and MCP-1. Immunohistochemistry analysis is ongoing to determine the molecular changes involved in tumor cell proliferation and apoptosis in response to arctigenin treatment. This study provides a promising natural compound to enhance chemoprevention of prostate cancer especially in obese patients. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans. Citation Format: Piwen Wang, Tanya Diaz, Susanne Henning, Jaydutt Vadgama. Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5253. doi:10.1158/1538-7445.AM2017-5253

Abstract 5249: Integrative analysis of transcriptomic, proteomic, and metabolomic data of Pten-knockout carcinogenic mouse prostate

Abstract The prostate-specific Pten-knockout (KO) mouse carcinogenesis model is highly desirable for prostate cancer chemoprevention studies due to its close resemblance of many histopathological features of human prostate cancer including disease progression from prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinomas. Here, we profiled the prostate proteome, transcriptome and aqueous metabolome of Pten-KO mice to identify reference molecular signatures that can be used for designing chemopreventive and/or therapeutic intervention and for selection of molecular biomarkers of responses to intervention. For proteomics, 4 pairs of whole prostates from Pten-KO mice (12-15 weeks of age, corresponding to high grade PIN) and their wild type littermate housed in same cages were obtained from the NCI Mouse Model Repository and analyzed by 8-plex iTRAQTM. For transcriptomic/microarray and metabolomic analyses, 3 additional matched pairs of prostate/tumor specimens at older age (22-20 weeks) were used. Proteomic and transcriptomic analyses using manual annotation methods with references from PubMed revealed top signatures that were up- and down-regulated by Pten deletion, particularly those implicated in immune function, inflammatory response, cancer, drug metabolism, cellular functions, prostate functions, and endoplasmic stress regulation. Similar to the manual annotation approach, each network analysis of 203 genes and 22 proteins (≥ 2- fold changes) by a bioinformatics software, Ingenuity Pathway Analysis (IPA) showed that inflammatory response, cellular movement, immune cell trafficking, immunological disease, and cancer were top 5 disease and biological functions in Pten-KO mice. Using references from PubMed, we manually assigned the unmapped prostate metabolites to functional categories, which included altered methionine-cysteine cycle fluxes and purine metabolites, increased nucleotide pools, cholesterol and polyamine synthesis and suppressed pools of sugar and choline derivatives, glycolysis intermediates, and purine bases. IPA network analysis of 25 metabolites (≥ 2- fold changes) revealed the biological functions related to molecular transport, amino acid metabolism, and small molecule biochemistry. In addition, we integrated transcriptomic, proteomic, and metabolomic data sets to identify latent biological relationships and to gain a comprehensive understanding of Pten-deficient prostate carcinogenesis. The integrative analysis predicted activation of inflammatory response and several central signaling nodes, such as IRF7, NF-κB, and IL-6. Collectively, the integrative analyses identify both active and latent reference molecular signatures and provide more insight into Pten-deficient prostate cancer than single omic approaches. Citation Format: Jinhui Zhang, Li Li, Sangyub Kim, LeeAnn Higgins, Yibin Deng, Christopher J. Kemp, Cheng Jiang, Junxuan Lu. Integrative analysis of transcriptomic, proteomic, and metabolomic data of Pten-knockout carcinogenic mouse prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5249. doi:10.1158/1538-7445.AM2017-5249

Fatty Acid Synthesis Intermediates Represent Novel Noninvasive Biomarkers of Prostate Cancer Chemoprevention by Phenethyl Isothiocyanate.

Increased de novo synthesis of fatty acids is a distinctive feature of prostate cancer, which continues to be a leading cause of cancer-related deaths among American men. Therefore, inhibition of de novo fatty acid synthesis represents an attractive strategy for chemoprevention of prostate cancer. We have shown previously that dietary feeding of phenethyl isothiocyanate (PEITC), a phytochemical derived from edible cruciferous vegetables such as watercress, inhibits incidence and burden of poorly differentiated prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) model. The current study was designed to test the hypothesis of whether fatty acid intermediate(s) can serve as noninvasive biomarker(s) of prostate cancer chemoprevention by PEITC using archived plasma and tumor specimens from the TRAMP study as well as cellular models of prostate cancer. Exposure of prostate cancer cells (LNCaP and 22Rv1) to pharmacologic concentrations of PEITC resulted in downregulation of key fatty acid metabolism proteins, including acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A). The mRNA expression of FASN and CPT1A as well as acetyl-CoA levels were decreased by PEITC treatment in both cell lines. PEITC administration to TRAMP mice also resulted in a significant decrease in tumor expression of FASN protein. Consistent with these findings, the levels of total free fatty acids, total phospholipids, triglyceride, and ATP were significantly lower in the plasma and/or prostate tumors of PEITC-treated TRAMP mice compared with controls. The current study is the first to implicate inhibition of fatty acid synthesis in prostate cancer chemoprevention by PEITC. Cancer Prev Res; 10(5); 279-89. ©2017 AACR.

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges.

Green tea catechins (GTCs) are a family of chemically related compounds usually classified as antioxidant molecules. Epidemiological evidences, supported by interventional studies, highlighted a more than promising role for GTCs in human prostate cancer (PCa) chemoprevention. In the last decades, many efforts have been made to gain new insights into the mechanism of action of GTCs. Now it is clear that GTCs’ anticancer action can no longer be simplistically limited to their direct antioxidant/pro-oxidant properties. Recent contributions to the advancement of knowledge in this field have shown that GTCs specifically interact with cellular targets, including cell surface receptors, lipid rafts, and endoplasmic reticulum, modulate gene expression through direct effect on transcription factors or indirect epigenetic mechanisms, and interfere with intracellular proteostasis at various levels. Many of the effects observed in vitro are dose and cell context dependent and take place at concentrations that cannot be achieved in vivo. Poor intestinal absorption together with an extensive systemic and enteric metabolism influence GTCs’ bioavailability through still poorly understood mechanisms. Recent efforts to develop delivery systems that increase GTCs’ overall bioavailability, by means of biopolymeric nanoparticles, represent the main way to translate preclinical results in a real clinical scenario for PCa chemoprevention.

Chemoprevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HGPIN): a systematic review and adjusted indirect treatment comparison.

BackgroundHigh-grade prostatic intraepithelial neoplasia (HGPIN) is the precursor or premalignant form of prostate cancer. At least 30% patients with a confirmed HGPIN will develop prostate cancer within 1 year after repeated biopsy. HGPIN patients are the appropriate at-risk population for chemoprevention strategies investigation against prostate cancer. However the commonly used chemoprevention agents that targeted on hormonal imbalance or lifestyle-related factors showed varied results in HGPIN patients.MethodsLiterature searches were conducted in PubMed, EMBASE and Cochrane library according to Cochrane guidelines before January 31st, 2017. Direct meta-analysis were performed to summarize the efficacy of candidate chemopreventative agents Dutasteride, Flutamide, Toremifene, Selenium, Green tea components, Lycopene and natural food products combination. Adjusted indirect meta-analyses were employed to compare the relative efficacy of these candidate chemoprevention agents head-to-head.ResultsThe overall incidence of prostate cancer in HGPIN was slightly decreased by chemoprevention agents (25.7% vs 31.5%, RR = 0.92, 95% CI: 0.83-1.03, P = 0.183), with minor heterogeneity (I2 = 22.3%, χ2 = 15.08, P = 0.237), but without statistical significance. Subgroup analysis showed that green tea catechins significantly decreased prostate cancer in HGPIN patients (7.60% vs 23.1%, RR = 0.39, 95% CI: 0.16-10.97, P P = 0.044), with moderate heterogeneity (I2 = 47.9%, χ2 = 1.92, P = 0.166). The adjusted indirect meta-analysis favored green tea catechins over other chemoprevention agents, and significantly when compared to natural food products combination (RR = 0.355, 95% CI: 0.134-0.934).ConclusionThe overall efficacy of chemoprevention agents in HGPIN patients is limited. But Green tea catechins showed the superiority to decrease prostate cancer in HGPIN patients.

Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer

Long noncoding RNAs (lncRNAs) have emerged as important in cancer development and progression. The impact of diet on lncRNA expression is largely unknown. Sulforaphane (SFN), obtained from vegetables like broccoli, can prevent and suppress cancer formation. Here we tested the hypothesis that SFN attenuates the expression of cancer-associated lncRNAs. We analyzed whole-genome RNA-sequencing data of normal human prostate epithelial cells and prostate cancer cells treated with 15 μM SFN or dimethylsulfoxide. SFN significantly altered expression of ~100 lncRNAs in each cell type and normalized the expression of some lncRNAs that were differentially expressed in cancer cells. SFN-mediated alterations in lncRNA expression correlated with genes that regulate cell cycle, signal transduction and metabolism. LINC01116 was functionally investigated because it was overexpressed in several cancers, and was transcriptionally repressed after SFN treatment. Knockdown of LINC01116 with siRNA decreased proliferation of prostate cancer cells and significantly up-regulated several genes including GAPDH (regulates glycolysis), MAP1LC3B2 (autophagy) and H2AFY (chromatin structure). A four-fold decrease in the ability of the cancer cells to form colonies was found when the LINC01116 gene was disrupted through a CRISPR/CAS9 method, further supporting an oncogenic function for LINC01116 in PC-3 cells. We identified a novel isoform of LINC01116 and bioinformatically investigated the possibility that LINC01116 could interact with target genes via ssRNA:dsDNA triplexes. Our data reveal that chemicals from the diet can influence the expression of functionally important lncRNAs, and suggest a novel mechanism by which SFN may prevent and suppress prostate cancer.

A Review of the Potential of Phytochemicals from Prunus africana (Hook f.) Kalkman Stem Bark for Chemoprevention and Chemotherapy of Prostate Cancer.

Prostate cancer remains one of the major causes of death worldwide. In view of the limited treatment options for patients with prostate cancer, preventive and treatment approaches based on natural compounds can play an integral role in tackling this disease. Recent evidence supports the beneficial effects of plant-derived phytochemicals as chemopreventive and chemotherapeutic agents for various cancers, including prostate cancer. Prunus africana has been used for generations in African traditional medicine to treat prostate cancer. This review examined the potential roles of the phytochemicals from P. africana, an endangered, sub-Saharan Africa plant in the chemoprevention and chemotherapy of prostate cancer. In vitro and in vivo studies have provided strong pharmacological evidence for antiprostate cancer activities of P. africana-derived phytochemicals. Through synergistic interactions between different effective phytochemicals, P. africana extracts have been shown to exhibit very strong antiandrogenic and antiangiogenic activities and have the ability to kill tumor cells via apoptotic pathways, prevent the proliferation of prostate cancer cells, and alter the signaling pathways required for the maintenance of prostate cancer cells. However, further preclinical and clinical studies ought to be done to advance and eventually use these promising phytochemicals for the prevention and chemotherapy of human prostate cancer.

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Background/Aims: Aspirin has been demonstrated to possess potent chemopreventive and anticancer effects on prostate cancer. However, the more detailed molecular mechanisms of aspirin to suppress prostate cancer cell invasion have not been clearly elucidated. Methods: Transwell assays were performed to evaluate the effects of aspirin on cell invasion. Matrix metalloproteinases (MMPs) and serine proteinases activities in cell media were examined by gelatin zymography and ELISA. In addition, inhibitor of κB (IκB) kinase-β (IKK-β) phosphorylation and IKK-β kinase activity were measured to assess the effects of aspirin on IKK-β activation. Results: We found that aspirin suppressed the invasion and attachment in human prostate cancer cells. Aspirin treatment significantly resulted in reduction of matrix metalloproteinase-9 (MMP-9) and upregulation of tissue inhibitors of metalloproteinase-1 (TIMP-1) activity, which are the proteolytic enzymes contributing to the degradation of extracellular matrix and basement membrane in cell invasion and metastasis. Our data further showed that aspirin was able to inhibit both urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression in the cells. In addition, aspirin treatment caused a strong decrease in nuclear factor-kappa B (NF-κB) activation, inhibitor of κB (IκB)-α phosphorylation together with translocation of NF-κB p65 to nucleus and IκB kinase (IKK)- β activation. Moreover, the inhibitory effects of aspirin on cell invasion were reversed by IKK-β overexpression, while the IKK inhibitor sensitizes the anti-invasive effect of aspirin in prostate cancer cells. Conclusion: The present research concluded that aspirin suppressed prostate cancer cell invasion by reducing MMP-9 activity and uPA expression through decreasing of IKK-β-mediated NF-κB activation, indicating that the ability of aspirin to inhibit cell invasion might be useful in the chemoprevention of metastatic prostate cancer.

Is There a Future for Chemoprevention of Prostate Cancer?

The outcome of the Selenium and Vitamin E Cancer Prevention Trial, demonstrating harm and no preventive activity of selenomethionine and α-tocopherol for prostate cancer, and the lack of approval by the FDA for the use of 5α-reductase inhibitors to prevent prostate cancer have cast doubt about the future of chemoprevention of prostate cancer. This article attempts to critically assess whether the notion that chemoprevention of prostate cancer has no future is warranted. Risk of prostate cancer is modifiable and chemoprevention of prostate cancer, particularly fatal/lethal cancer, is both needed and possible. However, the approach to prostate cancer-chemopreventive agent development has not followed a rational and systematic process. To make progress, the following steps are necessary: (i) identification of intermediate biomarkers predictive of fatal/lethal disease; (ii) development of a rational approach to identification of candidate agents, including high-throughput screening and generation of information on mechanism and biology of candidate agents and potential molecular targets; and (iii) systematic evaluation of the predictive value of preclinical models, phase II trials, and intermediate biomarkers for the outcome of phase III trials. New phase III trials should be based on adequate preclinical and phase II studies. Cancer Prev Res; 9(8); 642-7. ©2016 AACR.

Abstract 2626A: A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo

Abstract Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa, an herb widely used in traditional Chinese medicine to treat inflammation related diseases such as cough, cold and swelling of throat. The present study was designed to investigate whether arctigenin is a potent inhibitor of prostate cancer using both in vitro and xenograft mouse models. The treatments with arctigenin at lower doses (< 2μM) for 48h dose-dependently inhibited the proliferation of two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC-4, by 40-50% compared to control. There was no cytotoxicity observed in normal prostate epithelial PrEC cells with arctigenin doses up to 10μM. An intervention study was then conducted in severe combined immunodeficiency (SCID) mice to confirm the tumor-inhibitory effect of arctigenin in vivo. Male SCID mice (n = 10 per group) were inoculated with 5×10⁁5 LAPC-4 cells subcutaneously. One week later when tumors were palpable the intervention started. Mice were administered with arctigenin at 50mg/kg (LD) or 100mg/kg (HD) or vehicle control daily for 6 weeks by oral gavage. After 4 weeks of intervention the tumor growth was significantly inhibited by both of the arctigenin doses. After 6 weeks of intervention, the tumor volumes were reduced by 48% (LD arctigenin) and 67% (HD arctigenin) compared to control. There was no significant difference in food or water consumption or body weight among groups. An ELISA assay of growth factors demonstrates that arctigenin treatments significantly decreased the concentrations of VEGF, EGF, NGF-β, TNF-α, and FGF-β in tumor tissues compared to control. Western blot analysis revealed a significantly reduced expression of galectin-4 in tumor tissues by arctigenin treatment. Previous studies have shown that strong expression of galectin-4 can be induced in different types of cancer, associated with tumor growth and progression. A microRNA PCR array assay was performed to measure the tumor concentrations of 84 microRNAs involved in prostate cancer development and progression. A panel of microRNAs including miR-126 and miR-135 were identified to be responsive to arctigenin treatment. Further mechanistic investigation using tissue microarray assay is ongoing to measure the protein markers of proliferation and apoptosis in tumor tissues. This study provides a promising non-toxic agent to enhance chemoprevention of prostate cancer. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans. Citation Format: Piwen Wang, Susanne M. Henning, Jaydutt V. Vadgama. A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2626A.

Suppressed Sex Hormone Biosynthesis by Alkylresorcinols: A Possible Link to Chemoprevention

ABSTRACTAlkylresorcinols (ARs, 5-n-alkylresorcinols) are amphiphilic phenolic lipids in whole grain rye and wheat, with a long odd-numbered carbon chain. A preventive effect of whole grain diet on sex hormone-dependent cancers has been recognized, but the active component(s) or mechanisms are not known. We have investigated the effects of the ARs C15:0, C19:0, and C21:0, individually and in combination, on steroid hormone production by using the human adrenocortical cell line H295R. Decreased synthesis of dehydroepiandrosterone (DHEA), testosterone, and estradiol was demonstrated at low concentrations of C15:0 and C19:0. There were no indications of additive effects on steroid secretion from the combined treatment with equimolar concentrations of the three ARs. Gene expressions of CYP21A2, HSD3B2, and CYP19A1 were downregulated and CYP11A1 was upregulated by the ARs. The results on gene expression could not explain the effects on steroidogenesis, which may be due to direct effects on enzyme activities, such as inhibition of CYP17A1. Our results demonstrate suppressed synthesis of testosterone and estradiol by ARs suggesting a novel mechanism for ARs in the chemoprevention of prostate and breast cancer.

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer.

Prostate cancer (PCa), a hormonally-driven cancer, ranks first in incidence and second in cancer related mortality in men in most Western industrialized countries. Androgen and androgen receptor (AR) are the dominant modulators of PCa growth. Over the last two decades multiple advancements in screening, treatment, surveillance and palliative care of PCa have significantly increased quality of life and survival following diagnosis. However, over 20% of patients initially diagnosed with PCa still develop an aggressive and treatment-refractory disease. Prevention or treatment for hormone-refractory PCa using bioactive compounds from marine sponges, mushrooms, and edible plants either as single agents or as adjuvants to existing therapy, has not been clinically successful. Major advancements have been made in the identification, testing and modification of the existing molecular structures of natural products. Additionally, conjugation of these compounds to novel matrices has enhanced their bio-availability; a big step towards bringing natural products to clinical trials. Natural products derived from edible plants (nutraceuticals), and common folk-medicines might offer advantages over synthetic compounds due to their broader range of targets, as compared to mostly single target synthetic anticancer compounds; e.g. kinase inhibitors. The use of synthetic inhibitors or antibodies that target a single aberrant molecule in cancer cells might be in part responsible for emergence of treatment refractory cancers. Nutraceuticals that target AR signaling (epigallocatechin gallate [EGCG], curcumin, and 5α-reductase inhibitors), AR synthesis (ericifolin, capsaicin and others) or AR degradation (betulinic acid, di-indolyl diamine, sulphoraphane, silibinin and others) are prime candidates for use as adjuvant or mono-therapies. Nutraceuticals target multiple pathophysiological mechanisms involved during cancer development and progression and thus have potential to simultaneously inhibit both prostate cancer growth and metastatic progression (e.g., inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and proliferation). Given their multi-targeting properties along with relatively lower systemic toxicity, these compounds offer significant therapeutic advantages for prevention and treatment of PCa. This review emphasizes the potential application of some of the well-researched natural compounds that target AR for prevention and therapy of PCa.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Prostate Cancer Cells after Treatment with Xanthohumol-A Natural Compound Present in Humulus lupulus L.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. It has ability to selectively kill tumor cells showing no toxicity to normal cells. We tested the apoptotic and cytotoxic activities of xanthohumol, a prenylated chalcone found in Humulus lupulus on androgen-sensitive human prostate adenocarcinoma cells (LNCaP) in combination with TRAIL. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay (MTT) and lactate dehydrogenase assay (LDH). The expression of death receptors (DR4/TRAIL-R1 and DR5/TRAIL-R2) and apoptosis were detected using flow cytometry. We examined mitochondrial membrane potential (ΔΨm) by DePsipher reagent using fluorescence microscopy. The intracellular expression of proteins was evaluated by Western blotting. Our study showed that xanthohumol enhanced cytotoxic and apoptotic effects of TRAIL. The tested compounds activated caspases-3, -8, -9, Bid, and increased the expression of Bax. They also decreased expression of Bcl-xL and decreased mitochondrial membrane potential, while the expression of death receptors was not changed. The findings suggest that xanthohumol is a compound of potential use in chemoprevention of prostate cancer due to its sensitization of cancer cells to TRAIL-mediated apoptosis.

Grade-dependent Response to Finasteride in Early Prostate Cancer

Grade-dependent Response to Finasteride in Early Prostate Cancer

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study

Despite routine use of phosphodiesterase type 5 inhibitor totreat erectile dysfunction the role in prostate cancer chemoprevention remains unclear. Only a few studies have explored the link between phosphodiesterase type 5 inhibitor use andprostate cancer. We tested the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. REDUCE was a 4-year multicenter study testing the effect of daily dutasteride on prostate cancer risk in men with prostate specific antigen 2.5 to 10.0 ng/ml and negative biopsy who underwent study mandated biopsies at 2 and 4 years. The association of phosphodiesterase type 5 inhibitor with overall prostate cancer risk and disease grade (Gleason 2-6 and 7-10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis was performed to explore the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in North American men, given the significantly higher use of phosphodiesterase type 5 inhibitor in these subjects. Phosphodiesterase type 5 inhibitor was not associated with prostate cancer diagnosis (OR 0.90, 95% CI 0.68-1.20, p = 0.476), low grade disease (OR0.93, 95% CI 0.67-1.27, p=0.632) or high grade disease (OR 0.85, 95% CI0.51-1.39, p = 0.508). An inverse trend was seen between phosphodiesterase type 5 inhibitor and prostate cancer diagnosis in North American men but this was not statistically significant (OR 0.67, 95% CI 0.42-1.07, p = 0.091). Phosphodiesterase type 5 inhibitor use was not associated with decreased prostate cancer diagnoses on post-hoc analysis of REDUCE. In North American men, who had much higher baseline use of phosphodiesterase type 5 inhibitor, this treatment was associated with an inverse trend of prostate cancer diagnosis that approached but did not reach statistical significance.

MP04-01 METFORMIN USE AND RISK OF PROSTATE CANCER: RESULTS FROM THE REDUCE STUDY

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I1 Apr 2016MP04-01 METFORMIN USE AND RISK OF PROSTATE CANCER: RESULTS FROM THE REDUCE STUDY Tom Feng, Xizi Sun, Lauren Howard, Adriana Vidal, Daniel Moreira, Ramiro Castro-Santamaria, Gerald Andriole, and Stephen Freedland Tom FengTom Feng More articles by this author , Xizi SunXizi Sun More articles by this author , Lauren HowardLauren Howard More articles by this author , Adriana VidalAdriana Vidal More articles by this author , Daniel MoreiraDaniel Moreira More articles by this author , Ramiro Castro-SantamariaRamiro Castro-Santamaria More articles by this author , Gerald AndrioleGerald Andriole More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1936AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The role of metformin in prostate cancer chemoprevention remains unclear. Our aim was to evaluate the link between metformin use and prostate cancer diagnosis using the REDUCE study METHODS REDUCE was a 4-year, multicenter, randomized, double-blind, placebo-controlled study that followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years. In diabetic men from REDUCE, we tested the association between metformin use, use of other anti-diabetic medications, vs. no anti-diabetic medication use and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4-6, high-grade Gleason 7-10) using logistic regression. RESULTS Of the 540 diabetic men with complete data, 205 (38%) did not report use of any anti-diabetic medications, 141 (26%) reported use of at least one anti-diabetic medication other than metformin, and 194 (36%) reported use of metformin. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR=1.19, p=0.50), low- (OR=1.01, p=0.97), or high-grade (OR=1.80, p=0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin anti-diabetic medications and prostate cancer risk in both crude (OR=1.02, p=0.95) and multivariable analysis (OR=0.85, p=0.58). Furthermore, the interactions between anti-diabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all p>0.05). CONCLUSIONS Among diabetic men with a negative pre-study biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis. These findings do not support the use of metformin as prostate cancer chemoprevention in men with a negative biopsy. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e27 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Tom Feng More articles by this author Xizi Sun More articles by this author Lauren Howard More articles by this author Adriana Vidal More articles by this author Daniel Moreira More articles by this author Ramiro Castro-Santamaria More articles by this author Gerald Andriole More articles by this author Stephen Freedland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Epigenetic silencing and variable expression of SRD5A2 in specific compartments of human prostate.

38 Background: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. SRD5A2 can be expressed in both the epithelial and stromal compartments of the prostate gland. Previously, we have shown that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Here we determined whether variability of SRD5A2 expression occurs in specific compartments of prostate tissues. Methods: Frozen and formalin-fixed sections of human adult prostate tissue was used. Laser capture microdissection (LCM) was performed to obtain a pure population of epithelial and stromal cells. Approximately 500–600 excised cells were captured, and the methylation pattern of SRD5A2 was determined by DNA methylation pull-down assay kit. The expression of SRD5A2 protein was identified with immunohistochemistry and quantitated by ELISA. Results: In the whole prostate tissue, samples with high SRD5A2 immunoreactivity had much lower levels of SRD5A2 promoter methylation compared to those with low SRD5A2 immunoreactivity. DNA methylation assay for the epithelial compartment closely resembled the findings of the whole prostate tissue. In contrast, the samples from the stromal compartment showed uniform methylation irrespective of the methylation pattern in the epithelial compartment or the whole tissue. The expression of SRD5A2 protein quantitated by ELISA further showed that the variable expression of SRD5A2 is better determined by epithelial compartment expression. Conclusions: Our data suggests that variability of SRD5A2 expression is dependent on the methylation pattern and expression of SRD5A2 in the epithelial compartment and not the stroma. Therefore, if epithelial expression of SRD5A2 is more representative of the whole prostatic tissue expression, then it is logical that SRD5A2 inhibitor’s efficacy is dependent on involution of the epithelial cells. Our findings will have broad implications for the use of 5ARIs in the treatment of BPH and for the chemoprevention of prostate cancer. Grant support: NIH/R01 DK091353

Metformin use and risk of prostate cancer: results from the REDUCE study.

The role of metformin in prostate cancer chemoprevention remains unclear. REDUCE, which followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years, provides an opportunity to evaluate the link between metformin use and prostate cancer diagnosis with minimal confounding from screening biases. In diabetic men from REDUCE, we tested the association between metformin use, use of other antidiabetic medications, versus no antidiabetic medication use, and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4-6 and high-grade Gleason 7-10) using logistic regression. Of the 540 diabetic men with complete data, 205 (38%) did not report use of any antidiabetic medications, 141 (26%) reported use of at least one antidiabetic medication other than metformin, and 194 (36%) reported use of metformin. During the 4-year study, 122 men (23%) were diagnosed with prostate cancer. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR, 1.19; P = 0.50), low- (OR, 1.01; P = 0.96), or high-grade (OR, 1.83; P = 0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin antidiabetic medications and prostate cancer risk in both crude (OR, 1.02; P = 0.95) and multivariable analysis (OR, 0.85; P = 0.56). Furthermore, the interactions between antidiabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all P > 0.05). Among diabetic men with a negative prestudy biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis.

Anti-androgenic effects of flavonols in prostate cancer.

Dietary-derived agents, such as the flavonoids, are of particular interest for prostate cancer (PCa) chemoprevention as they may offer a favourable safety and side-effect profile. An agent that demonstrates action on the androgen receptor (AR) axis may have value for preventing or treating castrate-resistant PCa. Four main flavonols – quercetin, myricetin, kaempferol, and fisetin – have been demonstrated in laboratory studies to have chemopreventive action in both castrate-resistant and castrate-sensitive PCa models. Mechanisms of flavonol action on the AR axis in PCa have been proposed to be inhibition of the 5α-reductase enzymes, direct androgen competition, suppression of the AR complex and transactivation by coregulators such as c-Jun, Sp1, and the PI3K/Akt pathway. It is, however, still unclear with current levels of evidence whether AR axis-mediated effects can fully account for the flavonols’ chemopreventive action.

Abstract PR06: Effect of polyphenon E on progression to prostate cancer after diagnosis of high grade prostatic intraepithelial neoplasia

Abstract Importance: In recent years, several studies have suggested effectiveness of green tea catechins in prostate cancer (PCa) chemoprevention. With the exception of one trial from Italy, this has not been further tested in a randomized trial setting in high-risk men with atypical small acinar proliferation (ASAP) or high grade prostatic intraepithelial neoplasia (HGPIN). Objective: To determine whether the daily consumption of a standardized formulation of green tea catechins (Polyphenon E) supplement for 1 year reduces the rate of progression to PCa in men, diagnosed with HGPIN or ASAP. Additional objectives were to evaluate tolerance, lower urinary tract symptoms (LUTS) and quality of life (QOL). Design, setting and participants: A randomized, double-blinded trial was conducted from September 2008 to March 2014 at medical centers in the US targeting 97 men diagnosed HGPIN or ASAP, randomized to treatment (n=49) or control arm (n=48). Supplement or placebo was initiated within 3 months of initial biopsy and continued for 1 year. Intervention: Participants were block randomized by baseline diagnosis and study site to receive Polyphenon E (PolyE), a decaffeinated, standardized green tea catechin mixture, the main component of which is (−)-epigallocatechin-3-gallate (EGCG) at a dose of 400 mgs EGCG per day (200 mgs twice a day [BID]), or placebo. Main outcomes and measures: Rate of progression to PCa at one year in men treated with PolyE or placebo following diagnosis of HGPIN or ASAP; evaluation of tolerance, LUTS and QOL. Results: Overall, we did not observe a difference in the number of men who progressed to PCa in one year in the Poly E (4/49) arm compared to placebo arm(6/48). Secondary analyses of patients reaching a definitive endpoint revealed that among men with baseline diagnosis of HGPIN, a greater number progressed to ASAP or PCa in the placebo arm (10/25) compared to the PolyE arm (3/26; P<0.05). Interestingly, this result was largely driven by the fact that a significantly greater number of subjects with baseline HGPIN progressed to ASAP in the placebo arm (5/25) compared to men in the PolyE arm (0/26; P <0.05). In men with baseline diagnosis of ASAP, the rate of cancer diagnosis at the end of intervention were similar in both study arms. Men in the PolyE group treated for one year demonstrated a significant decrease in serum tPSA compared to those in the placebo group (-0.90 ng/mL;(95%CI:-1.67, -0.12; P<0.05). No significant differences in tolerance, LUTS or QOL were observed between the two groups. Conclusions and Relevance: Daily intake of a standardized, decaffeinated catechin mixture containing 400 mgs EGCG (200 mgs BID) for 1 year is well tolerated and appears to produce chemoprevention effects in the early stages (HGPIN to ASAP) of prostate carcinogenesis. These findings should be confirmed in a phase III clinical trial prior to recommending use in clinical settings. Trial Registration: Clinical Trials.gov Identifier: NCT00596011 Acknowledgement: The research study was funded by the National Institute of Health- National Cancer Institute R01 CA12060-01A1. We acknowledge the contributions of Anthony M. Neuger, Domenico Coppola, Binglin Yue, (Moffitt Cancer Center); Kyle Anderson (Minneapolis VA Medical Center, Minneapolis, MN); Eduard Trabulsi (Jefferson Medical College, Philadelphia, PA); Tajammul Fazili (Overton Brooks VA, Shreveport, LA); Edward Giovanucci (Harvard University); Gregory Zagaja (University of Chicago, Chicago, IL); Shahnjayla Connors (University of Washington, St. Louis, MO); Folake Odedina (University of Florida). External Data Monitoring Board: Omer Kucuk, (Emory University), Phyllis Bowen (Retired), and Steven Clinton (Ohio State University). Citation Format: Nagi B. Kumar, Julio Pow-Sang, Kathleen M. Egan, Philippe A. Spiess, Shohreh Dickinson, Raoul Salup, Mohamed Helal, Jerry McLarty, Christopher R. Williams, Fred Schreiber, Said Sebti, Aslam Kazi, Loveleen Kang, Gwen Quinn, Tiffany Smith, Karen Diaz, Ganna Chornokur, Theresa Crocker, Michael J. Schell. Effect of polyphenon E on progression to prostate cancer after diagnosis of high grade prostatic intraepithelial neoplasia. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR06.