Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBPalpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPalpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPalpha acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPBalpha recruits AR to activate transcription. C/EBPalpha-dependent trans-activation by AR also overrode suppression of AREs by C/EBPalpha elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBPalpha. This unique mechanism explains the functional coordination between AR and C/EPBalpha in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.
Study Type - Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Intermittent androgen deprivation therapy (ADT) involves cycling ADT, allowing hormonal recovery during off-treatment periods. This could lead to a better quality of life during off-treatment periods and could delay progression to castration resistance. Safety and feasibility of intermittent ADT have been shown but tolerability and health-related quality of life improvement have been suggested but questioned by others. Results from randomized trials, including relapsing or mixed populations, have suggested intermittent ADT to be as effective as continuous ADT. In this study of only metastatic patients, no statistical difference in either overall survival or progression-free survival was shown between intermittent and continuous ADT and suggests that intermittent might be as safe as continuous castration. It could be an option in highly responding and well-informed metastatic patients even if no clear benefit in health-related quality of life was shown. This intermittent modality could be of interest in metastatic patients with significant treatment-induced side-effects.
Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.
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Glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22) are two proteins playing a crucial physiological role in the maintenance of the multilamellar structure of peripheral myelin. We here demonstrate that the removal of circulating androgens by orchidectomy induces a significant decrease of the synthesis of Po and PMP22 in the rat sciatic nerve. In case of Po, this effect may be counteracted by the subsequent treatment with testosterone metabolites, dihydrotestosterone or 5alpha-androstan-3alpha,17beta-diol (3alpha-diol). Experiments have been consequently performed in order to evaluate the role of androgen receptor (AR) in the control of Po synthesis. In vivo treatment with flutamide (i.e., an antagonist of AR) induces a decrease of the synthesis of this myelin protein in the sciatic nerve of intact male rats confirming a role for this steroid receptor. On the contrary, PMP22 seems not to be under the control of AR, but a role for GABAA receptor may be proposed. This concept is based on the findings that: (a) only 3alpha-diol, which is able to interact with GABAA receptor, is effective in stimulating the synthesis of PMP22 in the sciatic nerve of castrated male rats, and (b) flutamide treatment is ineffective in decreasing the protein levels in intact male rats. The observations here reported clearly show similarities and dissimilarities with the effects exerted by other members of neuroactive steroid family, like for instance progesterone derivatives, which will be discussed in text.
Poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features.
Clinical data and models of human disease indicate that androgen receptor (AR) activity is essential for prostate cancer development, growth, and progression. The dependence of prostatic adenocarcinoma on AR signaling at all stages of disease has thereby been exploited in the treatment of disseminated tumors, for which ablation of AR function is the goal of first-line therapy. Although these strategies are initially effective, recurrent tumors arise with restored AR activity, and no durable treatment has yet been identified to combat this stage of disease. New insights into AR regulation and the mechanisms underlying resurgent AR activity have provided fertile ground for the development of novel strategies to more effectively inhibit receptor activity and prolong the transition to therapeutic failure.
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Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5β1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.
DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tumors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RT+TAB and who had nondiploid tumors had reduced survival after salvage androgen ablation.
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We examined the influence of androgens on fetal medial basal hypothalamic and preoptic area (MBH-POA) calbindin-D28K levels (via Western analysis) by treating pregnant rats with testosterone or flutamide, (an androgen receptor blocker). MBH-POA calbindin-D28K levels were significantly decreased in flutamide-treated male fetuses, whereas, MBH-POA calbindin-D28K levels were significantly increased in testosterone-treated female fetuses compared to controls. These results suggest that MBH-POA calbindin-D28K is modulated during prenatal development by androgens.
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Several exciting new forms of therapy for metastatic prostatic cancer have been introduced recently. Luteinizing hormone-releasing hormone (LH-RH) agonists paradoxically inhibit pituitary release of luteinizing hormone, resulting in a fall of serum testosterone to castrate levels within two to four weeks. These drugs have no cardiovascular side effects. A nonsteroidal antiandrogen, flutamide, may be as effective as orchiectomy in men with untreated metastatic disease and has the advantage of preserving potency in most men. In recent reports, combining the LH-RH agonist with an antiandrogen resulted in "total medical castration," which may substantially improve objective response rates and patient survival. Ketoconazole, an antifungal drug, also rapidly inhibits testicular and adrenal androgen synthesis and decreases plasma testosterone to castrate levels within 72 hours. In men with hormone-resistant disease, combination chemotherapy may produce an objective response rate of 50%. In men with severely painful bony metastasis, an inexpensive drug used in Paget's disease, etidronate disodium, may be palliative.
In the present work, the activity of mouse renal ornithine decarboxylase (ODC) from CBA female mice was used as a biological marker to detect (anti)androgenic activity of different groups of endocrine disruptors and steroids. Daily injections of testosterone or dihydrotestosterone (DHT) into 60 day old female mice for 4 days increased renal ODC activity in a dose-dependent manner that reached up to 100-fold (testosterone) or 250-fold (DHT) above the baseline when the highest dose, 200 microg/mouse, was used. Administration of flutamide concurrently with testosterone (75 microg/mouse) caused a potent decrease of ODC induction in a dose-dependent manner, suppressing the enzyme activity at the doses of 0.1 and 0.5 mg/mouse by about 88 and 95%, respectively. In contrast, estradiol at the doses of 0.5 and 1 mg/mouse induced a significant stimulation of renal ODC activity in a dose-dependent manner when it was given alone or in combination with testosterone. Using a sensitive increase in ODC activity in response to androgens as an end point, we did not detect an antiandrogenic effect of several antiandrogens, such as cyproterone acetate, spironolactone, p,p'DDE and vinclozolin. Also, none of these antiandrogens were able to change the basal level of renal ODC activity, with the exception of cyproterone acetate that at a dose of 0.1 mg/mouse stimulated ODC activity. The data obtained suggest that mouse renal ODC from CBA females is not strictly androgen-specific and cannot be used for estimation of antiandrogenic effects of compounds having an affinity to different types of receptors.
Decreased proliferation and PSA mRNA levels, and increased apoptosis were observed in most tumours. These early cellular responses were not correlated to each other and did not predict serum PSA response or cancer-specific survival. A nadir PSA level below 1 ng/ml predicted a longer cancer-specific survival after castration therapy.
A retrospective study was performed on 72 transurethral resection specimens from patients who subsequently underwent endocrine therapy for prostate cancer and were followed for 44 to 95 months. Progression-free interval was recorded. Distribution pattern and proportion of neuroendocrine cells were examined in transurethral resection specimens. Neuroendocrine cells were identified based on immunoreactivity for chromogranin A.
In the present study, we show that miR-34c is detected in mouse pachytene spermatocytes and continues to be highly expressed in spermatids. To explore the specific functions of miR-34c, we have established an in vivo model by transfecting miR-34c inhibitors into primary spermatocytes to study the loss-of-function of miR-34c. The results show that silencing of miR-34c significantly increases the Bcl-2/Bax ratio and prevents germ cell from apoptosis induced by deprivation of testosterone. Moreover, ectopic expression of the miR-34c in GC-2 cell trigger the cell apoptosis with a decreased Bcl-2/Bax ratio and miR-34c inhibition lead to a low spontaneous apoptotic ratio and an increased Bcl-2/Bax ratio. Furthermore, ectopic expression of miR-34c reduces ATF1 protein expression without affecting ATF1 mRNA level via directly binding to ATF1's 3'UTR, indicating that ATF1 is one of miR-34c's target genes. Meanwhile, the knockdown of ATF1 significantly decreases the Bcl-2/Bax ratio and triggers GC-2 cell apoptosis. Inhibition of miR-34c does not decrease the GC-2 cell apoptosis ratio in ATF1 knockdown cells.
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This study was designed to determine how to suppress behavioral effects of androgens with a pure non-steroidal antiandrogen, Hydroxyflutamide (OHF). The major dependent variable was yawning behavior of castrated adult male rhesus macaques. Injections of testosterone propionate (TP) increased yawning frequency and cessation of TP injections produced a decrease in yawning frequency. A similar decrease was observed with simultaneous injections of TP and OHF. It has been found that the dose of OHF injected subcutaneously should be 80 times that of TP to block the effects of either physiological or supraphysiological doses of TP.
It has previously been speculated that the androgen receptor antagonist flutamide produces behavioral effects that are not mediated by androgen receptors. These earlier studies were performed in intact rodents and thus, flutamide may have interfered with endogenous testosterone produced by the testes. The main objective of the present study was to examine whether flutamide induces anxiolytic-like behavior in castrated rats.
Histochemical and ultrastructural investigation of the prostate in baboons treated parenterally with saline revealed that the epithelial cells in the caudal prostatic lobe possess very high acid phosphatase activity, moderate nonspecific esterase activity and alkaline phosphatase activity, and little or no amino-peptidase or beta-glucuronidase activity. Only a few lipofuscin granules were found. Ultrastructurally, the epithelial cells had a characteristic polar appearance with a supranuclear zone dominated by large secretory vacuoles. Secretory granules were abundant in the apical zone. No clear difference was found between the cranial and the caudal prostate except that the acid phosphatase activity of the epithelial cells was much lower in the former. In baboons treated with estraumustine phosphate, diethylstilbestrol diphosphate, or with flutamide, i.e., drugs used in the treatment of advanced prostatic carcinoma, the epithelial cells in the caudal prostatic lobe showed a varying degree of atrophy, which was least in the flutamide-treated animals. The histologic changes were accompanied by only minor changes in the enzyme activities, but the number of histochemically demonstrable lipofuscin granules were substantially increased, a finding confirmed by electron microscopy. The drugs did not notably affect the cranial prostate. The findings showed that the caudal, but not the cranial, lobe of the prostate of the baboon resembles the human prostate and can be affected by drugs known to have a desirable effect on the carcinomatous human prostate.
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The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats.
Following maximum androgen blockade with an alternative nonsteroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial maximum androgen blockade. Even a partial response to second line maximum androgen blockade was associated with improved survival. Our data support the notion that responders to second line regimens are androgen independent but still hormonally sensitive.
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There was no association between incidence or rate of Hb decrease and race, age, or pretreatment prostate-specific antigen (PSA) levels. However, the recovery from anemia after completion of CAB in African-Americans was slower than in Whites in the Z+ group (P < 0.04). Whereas grade 1 hematologic toxicity may occur in < 5% of the patients with zoladex alone, and approximately 6% with flutamide alone, in our study 81% showed mild to pronounced anemia. Since anemia has not been observed after treatment with XRT alone or XRT followed by zoladex, we conclude that the anemia was due to CAB. Recognition of this side effect should avoid unnecessary diagnostic evaluations.
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Dehydroepiandrosterone (DHEA) may be a promising agent for postmenopausal osteoporosis (PMO), but its mechanism to modulate osteoblasts (OBs) is yet to be explained. To elucidate the effects of DHEA treatment on the ovariectomized (OVX) mice and its mechanisms, we evaluated the morphology of mice bone tissue and expression of proliferating cell nuclear antigen (PCNA) in the vertebrae-derived OB after having treated the OVX animals with DHEA. The results showed that DHEA administration increased the expression of PCNA in OB and changed the bone tissue morphometry of the PMO model. To further investigate this mechanism, the OB was isolated from neonatal mice calvariae by the enzyme-digested assay, exposed to DHEA, and then analyzed for ultrastructure, DNA content, early apoptotic cells, and phosphorylation of extracellular signal-regulated kinase 1/2. It was found that DHEA promoted proliferation and inhibited apoptosis of OB significantly, via mitogen-activated protein kinase signaling pathway independent of either androgen receptor or estrogen receptor, suggesting that it may exert roles via a DHEA-specific receptor directly, not by way of conversion to androgens or estrogens.
Low-dose pioglitazone (Pio), flutamide (Flu), metformin (Met) plus an oestro-progestagen is a novel polytherapy lowering total and visceral adiposity, and reducing carotid intima media thickness (IMT) in hyperinsulinaemic women with androgen excess, without changing their body mass index (BMI). In a search for mediators of PioFluMet's actions, we measured serum levels of visfatin and high molecular weight (HMW) adiponectin.
Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and two of its hydroxylated metabolites [5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)] were determined in male and female rats, in castrated males, and in rats pretreated with various steroid hormones. Male rats had a 2-fold higher SMZ plasma clearance than females, castrates, and males treated with flutamide (a testosterone antagonist). When castrated male rats were treated with testosterone or trenbolone, SMZ plasma clearance returned to normal values. Higher SMZ plasma clearance rates in the presence of androgens went together with higher urinary recoveries of the 6CH2OHSMZ metabolite. In hepatic microsomes of male rats lower apparent KM values, and higher Vmax values for 6CH2OHSMZ and 5OHSMZ formation were found than in microsomes of female rats. Castration or treatment of male rats with flutamide markedly reduced microsomal SMZ hydroxylation rates. Pretreatment of male or female rats with phenobarbital or triacetyl-oleandomycin had no effect on microsomal SMZ hydroxylation, whereas a continuous infusion with bovine somatotropin in male rats caused a marked decrease in SMZ hydroxylation rate. Finally, SMZ hydroxylation to 6CH2OHSMZ and 5OHSMZ in hepatic microsomes from male rats was strongly inhibited by monoclonal antibodies against P-4502C11. These results suggest that the male-specific P-4502C11 enzyme plays an important role in the hydroxylation of SMZ to 6CH2OHSMZ and 5OHSMZ in rats. SMZ seems a useful model compound to assess hormone effects on oxidative biotransformation (in vivo and in vitro) in rats.