Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1.

BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces-/- ) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.

Can local treatment prolong the sensitivity of metastatic prostate cancer to androgen deprivation or even prevent castration resistance?

PURPOSE: A number of observational clinical studies suggest that prior primary tumor treatment favorably influences the course of metastatic prostate cancer (PCa), but its mechanisms of action are still speculative. Here, we describe the long-lasting sensitivity to various forms of androgen deprivation in patients after radical prostatectomy (RP) for locally advanced PCa as one potential mechanism. METHODS: A consecutive series of 115 radical prostatectomies after inductive therapy for T4 prostate cancer was re-analyzed, and long-term survival, as well as recurrence patterns and responses to different forms of hormonal manipulation, were assessed. RESULTS: The estimated biochemical response-free, PCa-specific, and overall survival rates after 200 months were 20%, 65%, and 47% with a median overall survival of 156 months. The majority of patients, although not cured of locally advanced PCa (84/115), showed long-term survival after RP. PCa-specific and overall survival rates of these 84 patients with biochemical recurrence were 61% and 44% at 150 months. Long-term sensitivity to ADT was found to be the main reason for the favorable tumor-specific survival in spite of biochemical recurrence. CONCLUSIONS: Sensitivity to primary or secondary hormonal manipulation was the main reason for the long-term survival of patients who had not been cured by surgery only. The results suggest that treatment of the primary tumor-bearing prostate delays castration-resistant PCa and enhances the effect of hormonal therapies in a previously unknown manner. The underlying cellular and molecular mechanisms need to be explored in more detailed analyses, which could profoundly impact treatment concepts of locally advanced and metastatic PCa.

Evolving understanding and categorization of prostate cancer: preventing progression to metastatic castration-resistant prostate cancer: RADAR IV.

INTRODUCTION To interpret data and update the traditional categorization of prostate cancer in order to help treating clinicians make more informed decisions. These updates include guidance regarding how to best use next generation imaging (NGI) with the caveat that the new imaging technologies are still a work in progress. MATERIALS AND METHODS: Literature review. RESULTS: Critical goals in prostate cancer management include preventing or delaying emergence of distant metastases and progression to castration-resistant disease. Pathways for progression to metastatic castration-resistant prostate cancer (mCRPC) involve transitional states: nonmetastatic castration-resistant prostate cancer (nmCRPC), metastatic hormone-sensitive prostate cancer (mHSPC), and oligometastatic disease. Determination of clinical state depends in part on available imaging modalities. Currently, fluciclovine and gallium-68 (68Ga) prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) are the NGI approaches with the most favorable combination of availability, specificity, and sensitivity. PET imaging can be used to help guide treatment selection in most patients. NGI can help determine patients who are candidates for new treatments, most notably (next-generation androgen antagonists, eg, apalutamide, enzalutamide, darolutamide), that can delay progression to advanced disease. CONCLUSIONS: It is important to achieve a consensus on new and more easily understood terminology to clearly and effectively describe prostate cancer and its progression to health care professionals and patients. It is also important that description of disease states make clear the need to initiate appropriate treatment. This may be particularly important for disease in transition to mCRPC.

Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer.

A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3'-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease.

Long-term outcomes of combining prostate brachytherapy and metastasis-directed radiotherapy in newly diagnosed oligometastatic prostate cancer: A retrospective cohort study.

BACKGROUND: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial showed the survival benefit for prostate radiotherapy in newly diagnosed prostate cancer patients with a low metastatic burden. The result raises the next question whether additional radiotherapy to metastatic sites could improve the survival in those with a low metastatic burden. METHODS: We evaluated the efficacy and safety of prostate-directed radiotherapy (PDRT) with or without metastasis-directed radiotherapy (MDRT) in newly diagnosed oligometastatic patients who underwent combination of high-dose-rate prostate brachytherapy, external beam radiotherapy, and androgen deprivation therapy. Forty patients with bone metastasis and node positive prostate cancer were retrospectively analyzed. Of these, 22 (55%), 3 (7%), and 15 (38%) patients had N1M0, M1a, and M1b, respectively. Eighteen patients (45%) received MDRT to all metastatic sites. All patients initially underwent ≧6 months of androgen deprivation therapy. Oligometastatic disease was defined as presence of five or fewer metastatic lesions. Median follow-up period was 62.5 months. RESULTS: Of the 40 patients, the 5-year castration-resistant prostate cancer (CRPC)-free survival rate and cancer-specific survival was 64.4% and 87.9%, respectively. Pre- or post-treatment predictive value including prostate-specific antigen (PSA) at diagnosis ≥20 ng/mL, Gleason grade group 5, positive biopsy core rate ≥51%, PSA nadir level of ≥0.02 ng/mL after the radiotherapy, and no MDRT were significantly associated with progression to CRPC. Patients with MDRT had significantly higher probability of achieving a PSA level of <0.02 ng/mL than those without the therapy (88.8% vs 54.5%, P = 0.0354) and consequently had a better CRPC-free survival than those without the therapy (HR 0.319, 95%CI: 0.116-0.877). Comparing PDRT alone, PDRT with MDRT did not significantly increase the incidences of genitourinary and gastrointestinal toxicities. CONCLUSIONS: This single-institutional study revealed the feasibility of combining prostate brachytherapy and MDRT for newly diagnosed oligometastatic prostate cancer. This combined approach has potential to prolong CRPC-free survival.

The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

VNLG-152 is a novel retinamide (NR) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E (eIF4E) translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration-resistant prostate cancer (CRPC) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg-1 bw, respectively (P < 0.0001), vs. vehicle with no host toxicity. Strikingly, the expression of full-length androgen receptor (f-AR)/androgen receptor splice variant-7 (AR-V7), mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2), phosphorylated eIF4E and their associated target proteins, including prostate-specific antigen, cyclin D1 and Bcl-2, were strongly decreased in VNLG-152-treated tumors signifying inhibition of f-AR/AR-V7 and MNK-eIF4E signaling in VNLG-152-treated CWR22Rv1 tumors as observed in vitro. VNLG-152 also suppressed the epithelial to mesenchymal transition in CWR22Rv1 tumors as evidenced by repression of N-cadherin, ß-catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases (MMP-2 and MMP-9) with upsurge in E-cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justify its further development towards clinical trials.

Chemopreventive Potential of Ethanolic Extracts of Luobuma Leaves (Apocynum venetum L.) in Androgen Insensitive Prostate Cancer.

Luobuma (Apocynum venetum L. (AVL)) is a popular beverage in Asia and has been reportedly to be associated with the bioactivities such as cardiotonic, diuretic, antioxidative, and antihypertensive. However, its biofunction as chemoprevention activity is seldom addressed. Herein, we aimed to characterize the anti-androgen-insensitive-prostate-cancer (anti-AIPC) bioactive compounds of Luobuma, and to investigate the associated molecular mechanisms. Activity-guided-fractionation (antioxidative activity and cell survivability) of Luobuma ethanolic extracts was performed to isolate and characterize the major bioactive compounds using Ultra Performance Liquid Chromatography (UPLC), Liquid Chromatography-Mass Spectrometry (LC-MS), and Nuclear Magnetic Resonance (NMR). Plant sterols (lupeol, stigamasterol and ß-sitosterol) and polyphenolics (isorhamnetin, kaempferol, and quercetin) were identified. Lupeol, a triterpene found in the fraction (F8) eluted by 10% ethyl acetate/90% hexane and accounted for 19.3% (w/w) of F8, inhibited the proliferation of PC3 cells. Both lupeol and F8 induced G2/M arrest, inhibition of ß-catenin signaling, regulation of apoptotic signal molecules (cytochrome c, Bcl-2, P53, and caspase 3 and 8), and suppression DNA repair enzyme expression (Uracil-DNA glycosylase (UNG)). To our knowledge, our study is the first report that lupeol inhibited the expression of UNG to elicit the cytotoxicity against androgen-insensitive-prostate-cancer cells. Collectively, Luobuma, which contains several antitumor bioactive compounds, holds the potential to be a dietary chemopreventive agent for prostate cancer.

Silencing of CDC20 suppresses metastatic castration-resistant prostate cancer growth and enhances chemosensitivity to docetaxel.

The role of cell division cycle 20 (CDC20) was investigated in chemoresistance to decetaxel and the underlying mechanisms in metastatic castration-resistant prostate cancer (mCRPC). MTT assays were performed to determine effects of siRNA-mediated CDC20 knockdown on cell proliferation and anticancer activity of docetaxel. Western blot analyses were conducted to detect changes of Akt and Wnt signaling. Furthermore, in vivo growth of PCa was examined in nude mice treated with siCDC20 or docetaxel alone or in combination. CDC20 was overexpressed in mCRPC cells. Knockdown of CDC20 suppressed cell proliferation and enhanced anticancer effect of docetaxel with IC50 reducing from 0.358 to 0.188 µg/ml in PC3 cells and 0.307 to 0.162 µg/ml in DU145 cells (P<0.01). While no change of Akt signaling was observed, inhibition of Wnt/ß-catenin signaling was detected upon CDC20 silencing. Xenograft tumor growth was significantly reduced in nude mice by CDC20 inhibition. The additional treatment of siCDC20 achieved better anticancer effects than that of docetaxel alone. Silencing of CDC20 may be a new strategy to improve chemosensitization to docetaxel in mCRPC.

Antitumoral action of icaritin in LNCaP prostate cancer cells by regulating PEA3/HER2/AR signaling.

Human epidermal growth factor receptor type 2 (HER2) and androgen receptor (AR) are critical factors for prostate cancer (PCa) progression. These factors regulate tumor cell survival and proliferation, and remain as crucial drivers of castration-resistant PCa progression. Icaritin (ICT) is a prenyl flavonoid derived from the Epimedium genus, which has many biological and pharmacological effects. Using androgen-sensitive human prostate carcinoma LNCaP cell lines, we found that 35 µg/ml of ICT could inhibit more than 50% of cell proliferation, induce cell apoptosis, and lead to a strong G1 phase arrest by targeting cyclin-related proteins and suppressing the ability of cell invasion. Moreover, ICT exerts its potent anticancer efficacy by inducing polyomavirus enhancer activator 3 (PEA3) to inhibit the aberrantly activated HER2/AR signaling. In addition, after PEA3 expression was silenced by specific small-interference RNA, we found that both the ICT-inhibited effect on LNCaP cell proliferation and the ICT-induced cell apoptosis rate decreased. These results provide alternative mechanisms for the antitumor actions of ICT, indicating that ICT might be a promising therapeutic agent, as well as a preventive agent, for hormone therapy-resistant PCa.

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.

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.

While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.

Cyclin D1 silencing suppresses tumorigenicity, impairs DNA double strand break repair and thus radiosensitizes androgen-independent prostate cancer cells to DNA damage.

Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor formation and neo-angiogenesis in vivo. Depletion of cyclin D1 significantly radiosensitizes PCa cells by increasing the RT-induced DNA damages by affecting the NHEJ and HR pathways responsible of the DNA double-strand break repair. Following treatment of cells with RT the abundance of a biomarker of DNA damage, γ-H2AX, was dramatically increased in sh-cyclin D1 treated cells compared to shRNA control. Concordant with these observations DNA-PKcs-activation and RAD51-accumulation, part of the DNA double-strand break repair machinery, were reduced in shRNA-cyclin D1 treated cells compared to shRNA control. We further demonstrate the physical interaction between CCND1 with activated-ATM, -DNA-PKcs and RAD51 is enhanced by RT. Finally, siRNA-mediated silencing experiments indicated DNA-PKcs and RAD51 are downstream targets of CCND1-mediated PCa cells radioresistance. In summary, these observations suggest that CCND1 is a key mediator of PCa radioresistance and could represent a potential target for radioresistant hormone-resistant PCa.

Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer.

PURPOSE: To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. RESULTS: The mean patient age was 67.1±9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. CONCLUSIONS: Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms.

Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspase-dependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

Methylselenocysteine preventing castration-resistant progression of prostate cancer.

BACKGROUND: Castration-resistant progression of prostate cancer after androgen deprivation therapy remains a critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor activity is an established driver of castration-resistant progression, and upregulation of androgen receptor expression has been implicated to contribute to the resurgent androgen receptor activity. We reported previously that methylselenocysteine can decrease the expression and activity of androgen receptor. Here we investigated the ability of methylselenocysteine to inhibit castration-resistant progression of prostate cancer. METHODS: The regrowth of LNCaP prostate cancer xenografts after castration was monitored. The levels of prostate-specific antigen in mouse serum were measured by ELISA. Tumor cell proliferation and apoptosis were analyzed via Ki-67 immunohistochemistry and TUNEL assay, respectively. Intratumoral angiogenesis was assessed by immunohistochemistry staining of vascular endothelial growth factor and CD31. RESULTS: We showed that methylselenocysteine delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation. This was accompanied by decreased serum levels of prostate-specific antigen, inhibition of prostate cancer cell proliferation and tumor angiogenesis, as well as downregulation of androgen receptor and induction of apoptosis in the relapsed tumors. CONCLUSIONS: The present study represents the first to show the preclinical efficacy of methylselenocysteine in delaying castration-resistant progression of prostate cancer. The findings provide a rationale for evaluating the clinical application of combining methylselenocysteine with androgen deprivation therapy for the treatment of advanced prostate cancer.

[Lipid metabolism and castration resistant prostate cancer].

Epidemiological studies showed the inverse association between statin use and prostate cancer incidence, especially advanced stages, or mortality. Recent report on association of postdiagnostic use of statin with reduction of prostatic or all-cause mortality strengthened the evidence in this subject. Our basic research findings demonstrated multiple mechanisms of lipid on prostate cancer proliferations. We also showed the mechanism of statin action on prostate cancer cells via IGF1-receptor or LDL receptor cascades. These findings will serve the new strategy for progressive and castration resistant prostate cancer management.

Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1.

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.

Vitamin D receptor agonist EB1089 is a potent regulator of prostatic "intracrine" metabolism.

BACKGROUND: A contributing factor to the emergence of castrate resistant prostate cancer (CRPC) is the ability of the tumor to circumvent low circulating levels of testosterone during androgen deprivation therapy (ADT), through the production of "intracrine" tumoral androgens from precursors including cholesterol and dehydroepiandrosterone (DHEA). As these processes promote AR signaling and prostate cancer progression their modulation is required for disease prevention and treatment. METHODS: We evaluated the involvement of the vitamin D receptor ligand EB1089 in the regulation of genes with a role in androgen metabolism using the androgen dependent cell lines LNCaP and LAPC-4. EB1089 regulation of androgen metabolism was assessed using QRT-PCR, luciferase promoter assays, western blotting, enzyme activity assays, and LC-MS analyses. RESULTS: EB1089 induced significant expression of genes involved in androgen metabolism in prostate cancer cells. Real-Time PCR analysis revealed that VDR mediated significant regulation of CYP3A4, CYP3A5, CYP3A43, AKR1C1-3, UGT2B15/17, and HSD17B2. Data revealed potent regulation of CYP3A4 at the level of mRNA, protein expression and enzymatic activity, with VDR identified as the predominant regulator. Inhibition of CYP3A activity using the specific inhibitor ritonavir resulted in alleviation of the anti-proliferative response of VDR ligands in prostate cancer cells. Mass spectrometry revealed that overexpression of CYP3A protein in prostate cancer cells resulted in a significant increase in the oxidative inactivation of testosterone and DHEA to their 6-ß-hydroxy-testosterone and 16-α-hydroxy-DHEA metabolites, respectively. CONCLUSIONS: These data highlight a potential application of VDR-based therapies for the reduction of growth-promoting androgens within the tumor micro-environment.

[Value of intermittent androgen deprivation in the context of the current data situation]. / Stellenwert der intermittierenden Androgendeprivation im Kontext der aktuellen Datenlage.

Androgen deprivation therapy is an integral part of the treatment of advanced and progressive prostate cancer. Various prospective randomised trials have investigated whether or not temporary suspension of androgen deprivation might delay the emergence of castration resistant prostate cancer and concomitantly improve quality of life. Until now, no phase III trial has been able to prove that intermittent androgen deprivation might delay the development of castration resistant tumours. Data from previous trials, except for one study, did at least not show adverse effects on survival. Data on quality of life are inconsistent, showing a trend towards improved quality of life with IAD. German as well as European guidelines reflect IAD as an established constituent of day-to-day medical practice. This review is intended to provide a code of practice for an individualised treatment as based on recently published studies.