The hormonal sensitivity of prostate cancer has been exploited clinically since Huggins and Hodges established the suppressive effects of castration on prostate cancer. Despite over sixty years of research into alternate modalities, androgen deprivation therapy (ADT) has become the mainstay treatment for locally advanced and metastatic prostate cancer. Suppression of testosterone production, the primary goal of hormonal therapy, can be achieved by a multitude of treatments. The ideal timing, duration and composition of ADT remains undefined. At the present time, first-line therapy consists of orchiectomy, luteinizing hormone-releasing hormone (LHRH) analogues or complete androgen blockade (CAB). However, new combinations and treatment settings show promise for improving outcomes and decreasing toxicity. This article provides an overview of the hormonal therapies currently used in advanced prostate cancer.
Androgen Antagonists ; Castration ; Gonadotropin-Releasing Hormone ; Orchiectomy ; Prostatic Neoplasms ; Testosterone

OBJECTIVE: To explore potential therapeutic targets other than androgen-deprivation treatment for prostate cancer by screening the proteins induced by androgen at palmitoylation modification level in LNCaP cells. METHODS: The LNCaP cells were treated with androgen (Methyltrienolone, R1881, 5 nmol/L) or dimethyl sulfoxide (DMSO) for 24 h, and then labeled with alkynyl palmitic acid Alk-C16 (100 μmol/L). After that, the cells were collected, lysed, the total protein was extracted, agarose beads labeled with azide (1 mmol/L) were added, and the click-chemistry reaction was carried out at room temperature for 1 h. The covalent bond formed by click-chemistry reaction of azide and alkynyl group was used to enrich the palmitoylated proteins on agarose beads. Label-free quantitation (LFQ) was used to compare the protein palmitoylation level of R1881 treated and untreated cells to screen the proteins induced by androgen at palmitoylation modification level. RESULTS: In this experiment, 907 potential palmitoylated proteins (mascot score>2, P<0.05) were identified, among which 430 proteins had LFQ values not zero at least twice. Among the 430 proteins, the palmitoylation levels of 92 candidates were increased by androgen treatment, and their LFQ values were significantly upregulated (>1.5-fold, P<0.05) in ≥2 samples of androgen-treated vs. untreated LNCaP cells. We also used the software of cytoscape to classify the 92 proteins, and found that the known functional proteins of them could be divided into three categories: metabolism related, protein folding related and translation initiation related. Among them, metabolism related proteins included lipid metabolism (6), glucose metabolism (7) and respiratory electron transport chain (8), and a small amount of amino acid metabolism (2) and other metabolism related proteins (2). Notably, the ratio of LFQ of cytochrome b-c1 complex subunit 2 (UQCRC2) was significantly (>3-fold, P<0.05) higher in androgen-treated cells compared with untreated cells, indicating that the palmitoylation level of UQCRC2 was enhanced by androgen most significantly than that of others. The second was long-chain acyl CoA dehydrogenase (ACADVL) related to lipid metabolism and glucose 6-phosphate dehydrogenase (PGD) related to glucose metabolism, but the LFQ ratio of them was less than 3-fold. CONCLUSION The research on palmitoylation mechanism of metabolism, especially the proteins related to respiratory electron transport chain, will provide a new guidance for the diagnosis and treatment of prostate cancer and the development of targeted drugs.
Androgen Antagonists ; Androgens ; Humans ; Lipoylation ; Male ; Prostatic Neoplasms

Prostate cancer is among the most common malignancies in Western countries, and its incidence is rapidly rising in Asia where it was traditionally considered an uncommon tumor. Our understanding of the disease and management strategies continue to evolve. The first revolution of its treatment was in the 1940s when hormonal therapy was used to treat patients. The discovery of prostate-specific antigen (PSA) and the subsequent adoption of widespread PSA screening have made it possible to diagnose the disease early, but it was not until recently that the field realized that we had been overdiagnosing and overtreating a large number of men with indolent diseases that will not impact their quality of life or life expectancy. Distinguishing indolent tumors from aggressive ones remains a challenge, although recent advances in multiparametric MRI have given clinicians more confidence in choosing men for active surveillance. However, more need to be done to fundamentally understand the molecular and cellular bases that determine the biologic behavior of each of the tumors.
Androgen Antagonists ; Disease Progression ; Humans ; Male ; Prostatic Neoplasms/therapy*

Androgens control a broad range of physiological functions. The androgen receptor (AR), a steroid receptor that mediates the diverse biological actions of androgens, is a ligand inducible transcription factor. Abnormalities in the androgen signaling system result in many disturbances ranging from changes in gender determination and sexual development to psychiatric and emotional disorders. Androgen replacement therapy can improve many clinical conditions including hypogonadism and osteoporosis, but is limited by the lack of efficacious and safe therapeutic agents with easy delivery options. Recent progress in the area of gene regulation by steroid receptors and by selective receptor modulators provides an opportunity to examine if selective androgen receptor modulators (SARMs) could address some of the problems associated with current androgen therapy. Since the composition of the transcriptional initiation complex recruited by liganded AR determines the specificity of gene regulation, synthetic ligands aimed at initiating transcription of tissue and promoter specific genes offers hope for developing better androgen therapy. Establishment of assays that predict synthetic ligand activity is critical for SARM development. Advancement in high throughput compound screening and gene fingerprinting technologies, such as microarrays and proteomics, will facilitate and accelerate identification of effective SARMs.
Androgen Antagonists ; pharmacology ; Androgen Receptor Antagonists ; Androgens ; chemistry ; metabolism ; Chlormadinone Acetate ; analogs & derivatives ; pharmacology ; Humans ; Male ; Receptors, Androgen ; physiology ; Receptors, Cytoplasmic and Nuclear ; physiology ; Testosterone Congeners ; pharmacology

Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Androgen Antagonists/therapeutic use* ; Androgen Receptor Antagonists/therapeutic use* ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms, Castration-Resistant/genetics* ; Receptors, Androgen/drug effects*

Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling. However, the effect is short-lived, as nearly all tumours progress to a hormone-refractory (HR) state, a lethal stage of the disease. Intuitively, the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR tumours. However, there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours. AR signalling can be activated in HR tumours through several mechanisms. First, activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens. Also, mutations in the AR can change AR ligand specificity, thereby allowing it to be activated by non-steroids or anti-androgens. Finally, overexpression of the wild-type AR sensitizes itself to low concentrations of androgens. Therefore, drugs targeting AR signalling could still be effective in treating HRPC.
Androgen Antagonists ; therapeutic use ; Androgens ; physiology ; Humans ; Ligands ; Male ; Prostatic Neoplasms ; drug therapy ; physiopathology ; Receptors, Androgen ; physiology ; Signal Transduction ; physiology

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Several promising new AR-targeted therapies have been developed. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway. This review focuses on the functions of AR in prostate cancer and the development of CRPC and promising new agents against CRPC.
Androgen Antagonists ; Castration ; Dihydrotestosterone ; Drug Resistance ; Drug Therapy ; Humans ; Point Mutation ; Prostate ; Prostatic Neoplasms ; Receptors, Androgen ; Receptors, Steroid ; Testosterone

PURPOSE: To evaluate the characteristics of patients who received primary androgen deprivation therapy (PADT) for prostate cancer and the clinical efficacy of this treatment. MATERIALS AND METHODS: Two hundred forty patients treated by PADT were reviewed. These patients could not receive definitive therapy owing to old age, patient need, and medical comorbidity. The patients were divided into three groups according to the extent of prostate cancer: localized, locally advanced, and metastatic. Then, prostate-specific antigen (PSA) progression in these groups was analyzed. RESULTS: The median age of the patients was 73.0 years, and the median pretreatment PSA level was 47.0 ng/mL. Of the patients, 91.7% were treated with combined androgen blockade, and 8.3% were treated with monotherapy. Clinical factors for PSA progression were a PSA nadir and a high clinical stage. Estimated PSA recurrence-free median survival time in each group was 57, 24, and 12 months, respectively. A PSA nadir of >0.2 ng/mL and metastatic stage were independent factors for expecting a poor response to PADT (hazard ratio 4.26, p<0.001; and 2.60, p<0.001). CONCLUSIONS: Patients with localized or locally advanced prostate cancer who did not receive definitive therapy had lower PSA progression rates than those at metastatic stage during PADT. Further, a PSA nadir of < or =0.2 ng/mL showed better progression-free survival. Therefore, PADT can be another therapeutic option in well-selected patients with localized or locally advanced prostate cancer and PSA change should be checked carefully.
Androgen Antagonists ; Comorbidity ; Disease-Free Survival ; Humans ; Prostate ; Prostate-Specific Antigen ; Prostatic Neoplasms* ; Retrospective Studies*

PURPOSE: The aim of this study was to analyze the prognostic significance of pre- and post-treatment serum prostate-specific antigen (PSA) level, together with a variety of other clinicopathological parameters, in patients with metastatic prostate cancer receiving maximal androgen blockade (MAB). MATERIALS AND METHODS: The PSA levels before and during MAB, together with various clinicopathological parameters, were measured in 65 patients with newly diagnosed metastatic prostate cancer. The prognostic significance of these parameters, including the PSA level two and six months after MAB (PSA2MO and PSA6MO), a 50% reduction in the pretreatment PSA level after MAB (PSA50), the extent of disease (EOD), performance state, Gleason score and pretreatment hemoglobin, were analyzed by both univariate and multivariate tests. RESULTS: Of the forty-nine patients with a pretreatment PSA level of > or =50ng/ml, twenty-four (24/49, 48.9%) showed normalized (< or =4ng/ml) PSA2MO, and three of these (3/24, 12.5%) died of metastatic prostate cancer. Twenty-five patients (25/49, 51.1%) showed no normalization of the PSA2MO, and sixteen of these (16/25, 64%) died of metastatic prostate cancer. Of the patients with a pretreatment PSA level > or =50ng/ml, patients with a normalized PSA2MO showed a higher survival rate than those with a non-normalized PSA2MO from the univariate analysis using the Log-Rank test (p=0.0001), and PSA2MO was revealed as the most useful prognostic factor (p=0.022) from the multivariate analysis using the Cox proportional hazards regression model. CONCLUSIONS: A normalized (< or =4ng/ml) PSA level 2 months after MAB (PSA2MO) in metastatic prostate carcinoma was found to be the most useful prognostic factor in metastatic prostate cancer patients with a pretreatment PSA level of > or =50ng/ml.
Androgen Antagonists ; Humans ; Multivariate Analysis ; Neoplasm Grading ; Prostate* ; Prostate-Specific Antigen* ; Prostatic Neoplasms* ; Survival Rate

PURPOSE: We evaluated the effectiveness of second-line maximum androgen blockade (MAB) with an alternative antiandrogen in patients who relapsed after initial MAB. MATERIALS AND METHODS: We retrospectively analyzed 47 patients with prostate cancer who relapsed after initial MAB, including surgical or medical castration combined with antiandrogens, from January 1998 to December 2009. When the serum prostate-specific antigen (PSA) level was increased on three consecutive occasions, we discontinued the antiandrogen and then administered an alternative antiandrogen. Seven patients were assessed for antiandrogen withdrawal syndrome (AWS). The effect of the second-line MAB was evaluated by the serum PSA level, and response was subdivided into > or =50% and <50% PSA reductions from the baseline PSA at the start of second-line MAB. RESULTS: PSA reduction was observed in 32 patients (68.1%). Among them, 23 (48.9%) achieved > or =50% PSA reductions with a mean response duration of 13.4+/-5.4 months. Nine (19.2%) patients reached <50% PSA reductions with a mean response duration of 12.2+/-6.2 months. The time to nadir PSA level after first-line MAB in the > or =50% PSA reduction group, <50% PSA reduction group, and PSA elevation group was 15.6+/-12.9 months, 11.8+/-6.0 months, and 8+/-6.5 months, respectively. That is to say, it was significantly longer in the responder groups (p=0.038). CONCLUSIONS: Second-line MAB using an alternative antiandrogen is an effective treatment option before cytotoxic chemotherapy in patients who relapse after initial MAB.
Androgen Antagonists ; Castration ; Humans ; Prostate ; Prostate-Specific Antigen ; Prostatic Neoplasms ; Recurrence ; Retrospective Studies