Toward Bicalutamide Analogues with High Structural Diversity Using Catalytic Asymmetric Oxohydroxylation.

A catalytic enantioselective synthesis of bicalutamide derivatives with promising potentials in prostate cancer treatment has been disclosed. The key intermediates, α-hydroxy-ß-keto esters, were efficiently constructed through cinchoninium-mediated asymmetric oxohydroxylation of easily accessible alkenes with potassium permanganate. Good yields and high levels of asymmetric induction are achieved. This method provides a new synthetic route to bicalutamide analogues with high structural diversity, which will beneficially support subsequent structure-activity relationship studies and boost prostate cancer drug development.

Reversibility of Bicalutamide PSMA PET-Positive Gynecomastia With Androgen Deprivation Therapy.

ABSTRACT: A 78-year-old man receiving bicalutamide for prostate cancer was referred for a PSMA PET/CT scan to evaluate his gradually rising prostate-specific antigen level. The PSMA PET/CT revealed gynecomastia with radiotracer uptake in bilateral breast parenchyma, a known but rarely reported effect of bicalutamide monotherapy. This scan also demonstrated metastatic progression of his disease in bone and lymph nodes, and he was started on leuprolide injections. Three months after a decrease in his testosterone level, the radiotracer uptake in his breast tissue had resolved, demonstrating that PSMA-avid bicalutamide-induced gynecomastia is reversible.

Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study.

AIM: This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. METHODS: A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. RESULTS: In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer-related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer-related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50-1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50-818.50]). LIMITATIONS: EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. CONCLUSIONS: A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer-related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.

A Data-Distribution and Successive Spline Points based discretization approach for evolving gene regulatory networks from scRNA-Seq time-series data using Cartesian Genetic Programming.

The inference of gene regulatory networks (GRNs) is a widely addressed problem in Systems Biology. GRNs can be modeled as Boolean networks, which is the simplest approach for this task. However, Boolean models need binarized data. Several approaches have been developed for the discretization of gene expression data (GED). Also, the advance of data extraction technologies, such as single-cell RNA-Sequencing (scRNA-Seq), provides a new vision of gene expression and brings new challenges for dealing with its specificities, such as a large occurrence of zero data. This work proposes a new discretization approach for dealing with scRNA-Seq time-series data, named Distribution and Successive Spline Points Discretization (DSSPD), which considers the data distribution and a proper preprocessing step. Here, Cartesian Genetic Programming (CGP) is used to infer GRNs using the results of DSSPD. The proposal is compared with CGP with the standard data handling and five state-of-the-art algorithms on curated models and experimental data. The results show that the proposal improves the results of CGP in all tested cases and outperforms the state-of-the-art algorithms in most cases.

Structural insights into the mechanism of resistance to bicalutamide by the clinical mutations in androgen receptor in chemo-treatment resistant prostate cancer.

Despite advanced diagnosis and detection technologies, prostate cancer (PCa) is the most prevalent neoplasms in males. Dysregulation of the androgen receptor (AR) is centrally involved in the tumorigenesis of PCa cells. Acquisition of drug resistance due to modifications in AR leads to therapeutic failure and relapse in PCa. An overhaul of comprehensive catalogues of cancer-causing mutations and their juxta positioning on 3D protein can help in guiding the exploration of small drug molecules. Among several well-studied PCa-specific mutations, T877A, T877S and H874Y are the most common substitutions in the ligand-binding domain (LBD) of the AR. In this study, we combined structure as well as dynamics-based in silico approaches to infer the mechanistic effect of amino acid substitutions on the structural stability of LBD. Molecular dynamics simulations allowed us to unveil a possible drug resistance mechanism that acts through structural alteration and changes in the molecular motions of LBD. Our findings suggest that the resistance to bicalutamide is partially due to increased flexibility in the H12 helix, which disturbs the compactness, thereby reducing the affinity for bicalutamide. In conclusion, the current study helps in understanding the structural changes caused by mutations and could assist in the drug development process.Communicated by Ramaswamy H. Sarma.

Synthesis, molecular docking and biological evaluation of 1,2,4-oxadiazole based novel non-steroidal derivatives against prostate cancer.

Prostate cancer is one of the most prevalent cancers in men leading to second most death causing cancer in men. Despite the availability of multiple treatment still the prevalence is high for prostate cancer. Steroidal antagonists associated with poor bioavailability, side effects while non-steroidal antagonists show serious side effects like gynecomastia. Therefore, there is a need of potential candidate for the treatment of prostate cancer with better bioavailability, good therapeutic effect and minimal side effects. In the same context, we have designed the series, SP1-SP25 based 3-phenyl-5-styryl-1,2,4-oxadiazole as the core structure. We successfully synthesized all 25 molecules in this series and characterized them using 1H, 13C NMR, and mass spectroscopy. Subsequently, we conducted MTT assays using PC-3 cells and observed that all the compounds exhibited a dose-dependent decrease in cell viability. Notably, compounds SP04, SP16, and SP19 demonstrated a significant decrease in cell viability and exhibited potent activity compared to the other synthesized molecules and standard drug bicalutamide. Among them, SP04 emerged as the one of the most potent compounds with an IC50 value of 238.13 nM and an 89.99 % inhibition of PC-3 cells, compared to synthesized molecules and standard drug bicalutamide. Furthermore, we conducted ROS assays and androgen receptor inhibition assays using the potent compound SP04 and bicalutamide. The results indicated that SP04 increased ROS production and decreased androgen receptor expression dose-dependent manner. Additionally, we conducted a docking study to analyse the interaction patterns within the active site of the androgen receptor. ADMET analysis revealed that all the compounds exhibited favorable physicochemical properties and manageable toxicity profiles.

GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

OBJECTIVES: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). METHODS: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. RESULTS: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. CONCLUSIONS: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

Cytogenotoxic potential and toxicity in adult Danio rerio (zebrafish) exposed to chloramine T.

Background: Chloramine-T (CL-T) is a synthetic sodium salt used as a disinfectant in fish farms to combat bacterial infections in fish gills and skin. While its efficacy in pathogen control is well-established, its reactivity with various functional groups has raised concerns. However, limited research exists on the toxicity of disinfection by-products to aquatic organisms. Therefore, this study aims to assess the sublethal effects of CL-T on adult zebrafish by examining biomarkers of nucleus cytotoxicity and genotoxicity, acetylcholinesterase (AChE) inhibition, and histopathological changes. Methods: Male and female adult zebrafish (wildtype AB lineage) specimens were exposed to 70, 140, and 200 mg/L of CL-T and evaluated after 96 h. Cytotoxic and genotoxic effects were evaluated by estimating the frequencies of nuclear abnormalities (NA), micronuclei (MN), and integrated optical density (IOD) of nuclear erythrocytes. Histopathological changes in the gills and liver were assessed using the degree of tissue changes (DTC). AChE activity was measured in brain samples. Results and conclusions: At a concentration of 200 mg/L, NA increased, indicating the cytogenotoxic potential of CL-T in adult zebrafish. Morphological alterations in the nuclei were observed at both 70 and 200 mg/L concentrations. Distinct IOD profiles were identified across the three concentrations. There were no changes in AChE activity in adult zebrafish. The DTC scores were high in all concentrations, and histological alterations suggested low to moderate toxicity of CL-T for adult zebrafish.

Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants.

The median survival time of patients with an aggressive brain tumor, glioblastoma, is still poor due to ineffective treatment. The discovery of androgen receptor (AR) expression in 56% of cases offers a potential breakthrough. AR antagonists, including bicalutamide and enzalutamide, induce dose-dependent cell death in glioblastoma and glioblastoma-initiating cell lines (GIC). Oral enzalutamide at 20 mg/kg reduces subcutaneous human glioblastoma xenografts by 72% (p = 0.0027). We aimed to further investigate the efficacy of AR antagonists in intracranial models of human glioblastoma. In U87MG intracranial models, nude mice administered Xtandi (enzalutamide) at 20 mg/kg and 50 mg/kg demonstrated a significant improvement in survival compared to the control group (p = 0.24 and p < 0.001, respectively), confirming a dose-response relationship. Additionally, we developed a newly reformulated version of bicalutamide, named "soluble bicalutamide (Bic-sol)", with a remarkable 1000-fold increase in solubility. This reformulation significantly enhanced bicalutamide levels within brain tissue, reaching 176% of the control formulation's area under the curve. In the U87MG intracranial model, both 2 mg/kg and 4 mg/kg of Bic-sol exhibited significant efficacy compared to the vehicle-treated group (p = 0.0177 and p = 0.00364, respectively). Furthermore, combination therapy with 8 mg/kg Bic-sol and Temozolomide (TMZ) demonstrated superior efficacy compared to either Bic-sol or TMZ as monotherapies (p = 0.00706 and p = 0.0184, respectively). In the ZH-161 GIC mouse model, the group treated with 8 mg/kg Bic-sol as monotherapy had a significantly longer lifespan than the groups treated with TMZ or the vehicle (p < 0.001). Our study demonstrated the efficacy of androgen receptor antagonists in extending the lifespan of mice with intracranial human glioblastoma, suggesting a promising approach to enhance patient outcomes in the fight against this challenging disease.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Effect of Bicalutamide Combined with Docetaxel on Serum PSA and VEGF Levels in Patients with Advanced Prostate Carcinoma.

Objective: To investigate the effect of bicalutamide combined with docetaxel on the levels of prostate-specific antigen (PSA) in serum and vascular endothelial growth factor (VEGF) in patients with advanced prostate carcinoma (PCa). Methods: The clinical data of 103 patients with advanced PCa at our hospital between Feb. 2020 and Feb. 2021 were retrospectively analyzed, the 90 of whom screened by inclusion and exclusion criteria were finally chosen as research objects. They were divided into a control group and an experimental group according to the order of admission, with 45 cases in each group. The control group was treated with conventional treatment, while the experimental group underwent the combination of bicalutamide and docetaxel, and the clinical indices of the two groups were compared. Results: After treatment, the serum indices in the experimental group were remarkably lower than those in the control group (P < 0.001), with remarkably lower incidence of toxic and side effects (P < 0.05) and higher Expanded Prostate Cancer Index Composite (EPIC) scores (P < 0.001) in the experimental group than in the control group. Conclusion: The implementation of bicalutamide combined with docetaxel in patients with advanced PCa is effective in reducing the inflammatory expression and improving quality of life and has a higher safety profile. Compared with conventional treatment, this method is of high application value, and further studies will help establish a better solution for such patients.

Intensification strategies for cytostatics degradation by ozone-based processes in aqueous phase.

Over the past decade there has been an increasing concern on the presence of cytostatics (also known as anticancer drugs) in natural waterbodies. The conventional wastewater treatments seem not to be effective enough to remove them, and therefore new processes must be considered. This work investigates the performance of ozonation (O3), catalytic ozonation (O3/Fe2+) and peroxone (O3/H2O2) processes, under dark or UV radiation conditions, for the degradation of cytostatics of worldwide concern. The degradation of bicalutamide (a representative of recalcitrant cytostatics) was firstly assessed in batch and then in a tubular column reactor (continuous flow mode runs) using a wastewater treatment plant (WWTP) secondary effluent. Bicalutamide removal ranged between 66 % (O3) and 98 % (O3/H2O2/UV) in continuous flow mode runs, the peroxone process being the most effective. The performance of these processes was then assessed against a mixture of twelve cytostatics of worldwide concern spiked in the WWTP effluent (25-350 ng/L). After treatment, seven cytostatics were completely removed, whereas the five most recalcitrant ones were eliminated to an extent of 8-92 % in O3/H2O2, and 44-95 % in O3/H2O2/UV. Phytotoxicity tests revealed a noticeable reduction in the effluent toxicity, demonstrating the feasibility of these processes in realistic conditions as tertiary treatment.

Comparison of Cromolyn Sodium, Montelukast, and Zafirlukast Prophylaxis for Capsular Contracture.

BACKGROUND: Capsular contracture is the most common complication following breast augmentation. Recently, prophylaxis studies aiming to inhibit the release of profibrotic substances to prevent capsular contracture have gained in importance. This study investigated the effects of cromolyn sodium, montelukast, and zafirlukast on capsular contracture in a rat model. METHODS: Thirty female Wistar albino rats were randomly divided into five groups: control, sham, cromolyn sodium, montelukast, and zafirlukast. Intraperitoneal injections were administered daily to the sham (1 ml per day), cromolyn sodium (10 mg/kg per day), montelukast (10 mg/kg per day), and zafirlukast (1.25 mg/kg per day) groups 1 month before surgery. Miniature breast implants were then placed on the backs of the rats in each group. Injections were continued for the next 3 months. The rats were subsequently killed, and the capsules were harvested and assessed histopathologically. The histopathologic outcomes were acute inflammation status, inflammation severity, synovial metaplasia, foreign body reaction, mast cell count, and capsular thickness. RESULTS: The cromolyn sodium, montelukast, and zafirlukast groups had less acute inflammation and lower mean inflammation severity scores, foreign body reaction occurrence, mast cell counts, and capsular thickness than the control and sham groups ( p < 0.05). These parameters were better in the cromolyn sodium group than in the montelukast and zafirlukast groups ( p < 0.05). CONCLUSIONS: Cromolyn sodium appears to inhibit capsular contracture more efficiently than montelukast and zafirlukast. This report may be a pioneer study for the prophylactic use of cromolyn sodium in capsular contracture. CLINICAL RELEVANCE STATEMENT: The prophylactic administration of cromolyn sodium appears to reduce capsular contracture more efficiently than that of montelukast and zafirlukast. This report might constitute a pioneer study for the prophylactic use of cromolyn sodium in capsular contracture.

Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.

The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K+ recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca2+/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.

Salmon Protein Hydrolysate Potentiates the Growth Inhibitory Effect of Bicalutamide on Human Prostate Cancer Cell Lines LNCaP and PC3 by Modulating Iron Homeostasis.

Prostate cancer is a common cause of cancer death in men. In advanced stages of prostate cancer, androgen deprivation therapy (ADT) is initiated. Despite ADT, prostate cancers invariably progress to become androgen independent. A growing body of evidence implicates iron dysmetabolism in prostate cancer progression. A bioactive peptide-rich salmon protein hydrolysate (SPH) has previously been demonstrated to modulate iron homeostatic mechanisms. In the present study, the anticancer effect of SPH and bicalutamide co-treatment on LNCaP and PC3 prostate cancer cell proliferation was investigated. Our results found that SPH potentiates the anti-proliferative effect of bicalutamide in a dose-dependent manner for both cell lines. In the presence of 160 µg/mL SPH, co-treatment with 1.0 µM bicalutamide decreased LNCaP cells' relative colony survival from 25% (1.0 µM bicalutamide monotreatment) to 2% after culturing for 12 days. For PC3 cells, the relative colony survival diminished from 52% (10.0 µM bicalutamide) to 32% at an SPH concentration of 160 µg/mL. Gene expression profiling, employing quantitative real-time PCR, revealed that the inhibitory effects were related to significant FTH1 up-regulation with a concomitant TFRC down-regulation. In conclusion, our results provide in vitro evidence that SPH potentiates the growth inhibitory effect of bicalutamide on prostate cancer cells by modulating iron homeostasis mechanisms.

Preparation of responsive nano-adsorbent to near-infrared laser based on tungsten disulfide for bicalutamide extraction in human biological fluids.

Bicalutamide (BLT), a non-steroidal anti-androgen, is widely used in patients with advanced prostate cancer. This study aimed to synthesize a smart modified nano-adsorbent (SMNA) based on tungsten disulfide (WS2) for solid-phase extraction of BLT from human plasma and urine samples. Briefly, we increased drug loading capacity of SMNA through the polymer grafting onto the WS2 nano-sheets. Specifically, poly (N-vinylcaprolactam) as a thermo-sensitive polymer was incorporated into the synthesized polymer networks. SMNA was characterized via TGA, XRD, FE-SEM and FT-IR techniques. The influential variables including pH (6), adsorption temperature (30°C), and contact time (10 min) were carefully optimized. After drug loading process, SMNA was exposed to 808 nm near-infrared light, the shrinkage of the thermo-sensitive polymer took place quickly and the loaded BLT released in a short time of laser irradiation. In the end, the extracted BLT was analyzed with RP-HPLC-UV system (at 270 nm wavelength). The proposed method provided favorable linearity in the range of 0.1-15 µg/mL (R2 ≥ 0.9998), the LOD and LOQ values were obtained 0.01 µg/mL and 0.04 µg/mL, respectively. The mean results of drug recovery (at the three different concentrations) of the spiked BLT in human plasma (92.08%) and urine (94.17%) were satisfactory.