Bicalutamide

Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity...

Prostate cancer often develops anti-androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis-trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles...

When a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding domain, bound with antagonist. To address this open need, we leveraged molecular docking and molecular dynamics (MD) simulations to construct a structure of the WT-AR ligand binding domain bound with antagonist bicalutamide...

Prostate cancer is the most common cancer in men, and before it progresses and metastasizes, the anticancer drug bicalutamide is often administered to patients. Many cases of androgen-dependent prostate cancer develop resistance during treatment with bicalutamide. Therefore, the effect of bicalutamide on androgen-dependent LNCaP prostate cancer cells is of clinical interest. The aim of this study was to demonstrate the effects of the anticancer drug bicalutamide on LNCaP prostate cancer cells by using a proteomics approach...

Familial testotoxicosis is a disease with autosomal dominant inheritance that only affects men and which causes gonadotropin-independent precocious puberty. Although basal levels of luteinizing hormone and follicle-stimulating hormone are low, similar to what is expected in the pre-pubertal period, testosterone levels are high. Bicalutamide as an anti-androgen medication and anastrozole as an aromatase inhibitor have been proposed as agents that can be safely used in children. In the present study, we present the case of coexistent familial testotoxicosis and central precocious puberty induced by long-term androgen exposure in a patient aged 7...

OBJECTIVE: The objective of this retrospective study was to evaluate whether the effect of second-line therapy of flutamide after bicalutamide can predict the response to abiraterone. RESULTS: Thirty-four patients received abiraterone and 32 received enzalutamide after treatment with second-line flutamide for castration-resistant prostate cancer. Prostate-specific antigen-progression-free survival during treatment with abiraterone or enzalutamide was the endpoint...

Rational selection of polymers for amorphous drug stabilization is necessary for further successful development of solid dispersion technology. In this paper we investigated the effect of polymer chain length on the inhibition of amorphous drug recrystallization. To consider this problem we prepared a drug-polymer blends (in 10:1 drug to polymer ratio) containing bicalutamide (BIC) and polyvinylpyrrolidone (PVP) with different chain lengths K10, K30, K90. We applied broadband dielectric spectroscopy to compare the molecular dynamics of investigated samples and thoroughly recognize their crystallization tendencies from supercooled liquid state...

PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown. METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR...

PURPOSE OF REVIEW: Our aim is to review the steps of diagnosis and management of gynecomastia with a special focus on treatment of gynecomastia associated with androgen deprivation therapy for prostate cancer. RECENT FINDINGS: Recent studies investigating tamoxifen and radiation therapy for both therapy and prophylaxis of bicalutamide-induced gynecomastia are reviewed. Gynecomastia is a common clinical problem, affecting between one and two thirds of middle-aged men...

AR-mediated androgen signaling plays a key role in female reproductive system. Granulosa-lutein cells (GCs) are the main sites for expression of androgen receptor (AR). There is also a close relation between AKT signaling and AR. Here, we assayed the role for a synthetic AR ligand methyltrienolone (R1881) in expressions of AKTs and AR. Controlled ovarian hyperstimulation (COH) was performed in 20 normal women. Mural GCs were isolated by filtration method, cultured, and passaged. Then, the cells were starved for 48 h with 10% charcoal stripped FBS...

eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset)...

Therapies designed to reduce androgen production or receptor activation are effective in limiting prostate tumor growth. However, prolonged treatment with anti-androgen therapies results in the progression of prostate cancers into an androgen refractory state. Neuroendocrine differentiation (NED) has been associated with the progression of prostate cancers to an androgen resistant phenotype. In this work we investigated the effect of disrupting androgen receptor signaling in promoting NED of prostate carcinoma cells and whether it is accompanied by an increase in T-type Ca2+ channel expression...

PURPOSE: Antiandrogens inhibit the androgen receptor (AR) and play an important role in the treatment of prostate cancer (PC). This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of PC. MATERIALS AND METHODS: We searched PubMed® for clinical trials with the search terms "antiandrogens" and "prostate cancer" combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with PC...

Objective: To investigate the clinical effects of integrated traditional Chinese and Western medicine in the treatment of castration-resistant prostate cancer (CRPC). METHODS: A total of 54 CRPC patients were randomly divided into a control and a trial group, all treated by endocrine therapy (oral Bicalutamide at 50 mg per d plus subcutaneous injection of Goserelin at 3.6 mg once every 4 wk) and chemotherapy (intravenous injection of Docetaxel at 75 mg/m2 once every 3 wk plus oral Prednisone at 5 mg bid), while the latter group by Fuyang Huayu Prescription (a Traditional Chinese Medicine ［TCM］ prescription for tonifying yang and dispersing blood stasis) in addition, for a course of 24 weeks...

Background: Salvage treatments for biochemical relapse (BCR) after radical prostatectomy (RP) have several problems in terms of indications or adverse events. We studied the possibility of 2 years of bicalutamide monotherapy for BCR after RP. Methods: Patients who showed BCR (prostate-specific antigen (PSA) ≥ 0.2 ng/ml) after RP were recruited. Protocol treatment was planned as 2 years of bicalutamide (80 mg/day) followed by observation. Protocol treatment failure was defined as PSA re-elevation of ≥0...

The large-conductance Ca2+ -activated K+ channel KCa 1.1 plays an important role in the promotion of breast cancer cell proliferation and metastasis. The androgen receptor (AR) is proposed as a therapeutic target for AR-positive advanced triple-negative breast cancer. We herein investigated the effects of a treatment with antiandrogens on the functional activity, activation kinetics, transcriptional expression, and protein degradation of KCa 1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, voltage-sensitive dye imaging, and whole-cell patch clamp recording...

Prostate adenocarcinoma is a common urologic malignant neoplasm in man. Distant cutaneous metastases (CMs) of prostate carcinoma are extremely rare with a reported incidence of 0.36% and usually they occur late. Clinically, cutaneous metastasis of prostate carcinoma can mimic other skin conditions such as cellulitis, sebaceous cyst, zosteriform lesions, telangectasias, and more, resulting in a poor recognition. Few cases of true cutaneous metastatic prostate carcinoma exist in the literature. We present a case, where the first sign of carcinoma of the prostate was CM over the anterior abdominal wall...

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues...

BACKGROUND: The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment...

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6...