-
Molecular Medicine Reports Feb 2023Anti‑androgen drugs are the standard pharmacological therapies for treatment of non‑metastatic prostate cancer (PCa). However, the response of PCa cells may depend...
Anti‑androgen drugs are the standard pharmacological therapies for treatment of non‑metastatic prostate cancer (PCa). However, the response of PCa cells may depend on the anti‑androgen used and often patients become resistant to treatment. Thus, studying how the anti‑androgen drugs affect oncogenes expression and action and the identification of the best strategy for combined therapies are essential to improve the efficacy of treatments. The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) is an oncogene associated with PCa progression and aggressiveness, although its relationship with the androgen receptor signaling remains to be elucidated. The present study aimed to evaluate the effect of anti‑androgens in regulating STEAP1 expression and investigate whether silencing STEAP1 can make PCa cells more sensitive to anti‑androgen drugs. For this purpose, wild‑type and STEAP1 knockdown LNCaP cells were exposed to bicalutamide, enzalutamide and apalutamide. Bicalutamide decreased the expression of STEAP1, but enzalutamide and apalutamide increased its expression. However, decreased cell proliferation and increased apoptosis was observed in response to all drugs. Overall, the cellular and molecular effects were similar between LNCaP wild‑type and LNCaP‑STEAP1 knockdown cells, except for c‑myc expression levels, where a cumulative effect between anti‑androgen treatment and STEAP1 knockdown was observed. The effect of STEAP1 knockdown alone or combined with anti‑androgens in c‑myc levels is required to be addressed in future studies.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Nitriles; Androgen Antagonists; Prostatic Neoplasms, Castration-Resistant; Antigens, Neoplasm; Oxidoreductases
PubMed: 36660947
DOI: 10.3892/mmr.2023.12939 -
European Journal of Medicinal Chemistry Aug 2016Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the...
Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
Topics: Anilides; Antineoplastic Agents; Benzamides; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Drug Resistance, Neoplasm; Humans; Male; Microsomes, Liver; Molecular Docking Simulation; Molecular Dynamics Simulation; Nitriles; Permeability; Phenylthiohydantoin; Prostatic Neoplasms; Protein Conformation; Receptors, Androgen; Tosyl Compounds
PubMed: 27131065
DOI: 10.1016/j.ejmech.2016.04.052 -
Chemosphere May 2024The degradation of three anti-cancer drugs (ADs), Capecitabine (CAP), Bicalutamide (BIC) and Irinotecan (IRI), in ultrapure water by ozonation and UV-irradiation was...
The degradation of three anti-cancer drugs (ADs), Capecitabine (CAP), Bicalutamide (BIC) and Irinotecan (IRI), in ultrapure water by ozonation and UV-irradiation was tested in a bench-scale reactor and AD concentrations were measured through ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). A low-pressure mercury UV (LP-UV) lamp was used and degradation by UV (λ = 254 nm) followed pseudo-first order kinetics. Incident radiation in the reactor was measured via chemical actinometry using uridine. The quantum yields (φ) for the degradation of CAP, BIC and IRI were 0.012, 0.0020 and 0.0045 mol Einstein, respectively. Ozone experiments with CAP and IRI were conducted by adding ozone stock solution to the reactor either with or without addition of tert-butanol (t-BuOH) as radical quencher. Using this experimental arrangement, no degradation of BIC was observed, so a semi-batch setup was employed for the ozone degradation experiments of BIC. Without t-BuOH, apparent second order reaction rate constants for the reaction of the ADs with molecular ozone were determined to be 3.5 ± 0.8 ∙ 10 L mol s (CAP), 7.9 ± 2.1 ∙ 10 L mol s (BIC) and 1.0 ± 0.3 ∙ 10 L mol s (IRI). When OH-radicals (∙OH) were quenched, rate constants were virtually the same for CAP and IRI. For BIC, a significantly lower constant of 1.0 ± 0.5 ∙ 10 L mol s was determined. Of the tested substances, BIC was the most recalcitrant, with the slowest degradation during both ozonation and UV-irradiation. The extent of mineralization was also determined for both processes. UV irradiation was able to fully degrade up to 80% of DOC, ozonation up to 30%. Toxicity tests with Daphnia magna (D. magna) did not find toxicity for fully degraded solutions of the three ADs at environmentally relevant concentrations.
Topics: Ultraviolet Rays; Ozone; Nitriles; Water Pollutants, Chemical; Irinotecan; Anilides; Capecitabine; Tosyl Compounds; Antineoplastic Agents; Kinetics; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid
PubMed: 38604516
DOI: 10.1016/j.chemosphere.2024.141780 -
Translational Andrology and Urology Dec 2022
PubMed: 36632149
DOI: 10.21037/tau-22-765 -
International Journal of Endocrinology 2023Although prostate cancer patients initially respond to androgen deprivation therapy, most patients progress to a resistant phenotype. Castration resistance is due, in...
BACKGROUND
Although prostate cancer patients initially respond to androgen deprivation therapy, most patients progress to a resistant phenotype. Castration resistance is due, in part, to intratumoral and/or adrenal synthesis of androgens, overexpression or mutation of the androgen receptor (AR), stabilization of AR by chaperones, and ligand-independent activation of AR. Increasing evidence also links disruption of calcium homeostasis to progression of prostate cancer. Our previous study shows that heavy metal cadmium activates the AR through a ligand-independent mechanism. Cadmium mimics calcium in biological systems due to their similar ionic charge and radius. This study determines whether calcium activates AR and whether first- and second-generation antiandrogens block the ability of calcium to activate the receptor.
METHODS
The expression of androgen-responsive genes and calcium channels was measured in prostate cells using a quantitative real-time polymerase chain reaction assay. Cell growth was measured.
RESULTS
To ask whether calcium activates AR, prostate cells were treated with calcium in the absence and presence of the first-generation antiandrogens hydroxyflutamide and bicalutamide and the second-generation antiandrogen enzalutamide, and the expression of androgen-responsive genes and cell growth was measured. In the normal PWR-1E cells and HEK293T cells transiently expressing AR, treatment with calcium increased the expression of androgen-responsive genes by approximately 3-fold. The increase was blocked by enzalutamide but was not consistently blocked by the first-generation antiandrogens. In LNCaP cells which contain a mutant AR, treatment with calcium also increased the expression of androgen-responsive genes by approximately 3-fold, and the increase was more effectively blocked by enzalutamide than by hydroxyflutamide or bicalutamide. Treatment with calcium also increased cell growth that was blocked by enzalutamide. To ask whether dysregulation of calcium channels is associated with castration resistance, calcium channels were measured in the normal PWR-1E prostate cells, the hormone-responsive LNCaP cells, and the castration-resistant VCaP and 22RV1 cells. Compared to normal prostate cells, the hormone-responsive and hormone-resistant cells overexpressed several calcium channels.
CONCLUSIONS
The results of this study show that calcium activates AR and increases cell growth and that calcium channels are overexpressed in hormone-responsive and hormone-resistant prostate cancer cells. Taken together, the results suggest a novel role of calcium in the castration-resistant phenotype.
PubMed: 38131032
DOI: 10.1155/2023/9907948 -
International Journal of Radiation... Jun 2022CHHiP is a randomized trial evaluating moderately hypofractionated radiation therapy for treatment of localized prostate cancer. Of all participants, 97% of them had...
Nonrandomized Comparison of Efficacy and Side Effects of Bicalutamide Compared With Luteinizing Hormone-Releasing Hormone (LHRH) Analogs in Combination With Radiation Therapy in the CHHiP Trial.
PURPOSE
CHHiP is a randomized trial evaluating moderately hypofractionated radiation therapy for treatment of localized prostate cancer. Of all participants, 97% of them had concurrent short-course hormone therapy (HT), either luteinizing hormone-releasing hormone analog (LHRHa) or 150 mg of bicalutamide daily. This exploratory analysis compares efficacy and side effects in a nonrandomized comparison.
METHODS AND MATERIALS
In our study, 2700 patients received LHRHa and 403 received bicalutamide. The primary endpoint was biochemical/clinical failure. Groups were compared with Cox regression adjusted for various prognostic factors and stratified by radiation therapy dose. A key secondary endpoint was erectile dysfunction (ED) assessed by clinicians (using scores from Late Effects on Normal Tissues: Subjective/Objective/Management [LENT-SOM] subjective erectile function for vaginal penetration) and patients (single items within the University of California-Los Angeles Prostate Cancer Index [UCLA PCI] and Expanded Prostate Cancer Index Composite [EPIC]-50 questionnaires) at 2 years and compared between HT regimens by χ trend test.
RESULTS
Bicalutamide patients were significantly younger (median 67 vs 69 years LHRHa). Median follow-up was 9.3 years. There was no difference in biochemical or clinical failure with an adjusted hazard ratio or 0.97 (95% confidence interval, 0.77-1.23; P = .8). At 2 years, grade ≥2 LENT-SOM ED was reported in significantly more LHRHa patients (313 out of 590; 53%) versus bicalutamide (17 out of 68; 25%) (P < .0001). There were no differences in ED seen with UCLA-PCI and EPIC-50 questionnaires.
CONCLUSIONS
In this nonrandomized comparison, there was no evidence of a difference in efficacy according to type of HT received. Bicalutamide preserved clinician assessed (LENT-SOM) erectile function at 2 years but patient-reported outcomes were similar between groups.
Topics: Androgen Antagonists; Anilides; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Gonadotropin-Releasing Hormone; Humans; Male; Nitriles; Percutaneous Coronary Intervention; Prostatic Neoplasms; Tosyl Compounds
PubMed: 35017008
DOI: 10.1016/j.ijrobp.2021.12.160 -
Biomolecules Nov 2022Bicalutamide (BCL) is a nonsteroidal antiandrogen drug that represents an alternative to castration in the treatment of prostate cancer, due to its relatively long...
Bicalutamide (BCL) is a nonsteroidal antiandrogen drug that represents an alternative to castration in the treatment of prostate cancer, due to its relatively long half-life and tolerable side effects. However, it possesses a very low water solubility that can affect its oral bioavailability. In this work, we developed inclusion complexes of BCL with the highly soluble hydroxypropyl-β-cyclodextrin (HP-β-CyD) and sulfobutylether-β-cyclodextrin (SBE-β-CyD) to increase the water solubility and anticancer activity of BCL. The inclusion complexes were prepared using the freeze-drying method and were then characterized in a solid state via differential scanning calorimetry and X-ray analysis and in solution via phase-solubility studies and UV-vis and NMR spectroscopy. The BCL/HP-β-CyD and BCL/SBE-β-CyD inclusion complexes were amorphous and rapidly dissolved in water. Both the H-NMR spectra and molecular modeling studies confirmed the penetration of the 2-(trifluoromethyl)benzonitrile ring of BCL within the cavity of both cyclodextrins (CyDs). Due to the consistent improvement of the water solubility of BCL, the inclusion complexes showed higher antiproliferative activity toward the human prostate androgen-independent cell lines, DU-145 and PC-3, with respect to free BCL. These results demonstrate the ability of HP-β-CyD and SBE-β-CyD to complex BCL, permitting the realization of liquid formulations with potentially high oral bioavailability and/or possible parenteral administration.
Topics: Male; Humans; Cyclodextrins; Nitriles; Solubility; 2-Hydroxypropyl-beta-cyclodextrin; Water
PubMed: 36421730
DOI: 10.3390/biom12111716 -
The American Journal of Case Reports 2014Male, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy
PATIENT
Male, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy
MEDICATION
Casodex Clinical Procedure: - Specialty: Oncology.
OBJECTIVE
Adverse events of drug therapy.
BACKGROUND
Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature.
CASE REPORT
An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days.
CONCLUSIONS
While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.
PubMed: 24967002
DOI: 10.12659/AJCR.890679 -
Disease Markers 2022To investigate the effect of bicalutamide combined with docetaxel on the levels of prostate-specific antigen (PSA) in serum and vascular endothelial growth factor (VEGF)...
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 ( < 0.001), with remarkably lower incidence of toxic and side effects ( < 0.05) and higher Expanded Prostate Cancer Index Composite (EPIC) scores ( < 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.
Topics: Anilides; Carcinoma; Docetaxel; Humans; Male; Nitriles; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Retrospective Studies; Tosyl Compounds; Vascular Endothelial Growth Factor A
PubMed: 36033830
DOI: 10.1155/2022/4506350 -
Frontiers in Pharmacology 2015Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current clinically used antiandrogens such as flutamide,... (Review)
Review
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current clinically used antiandrogens such as flutamide, bicalutamide, and newly approved enzalutamide mainly target the hormone binding pocket (HBP) of AR. However, over time, drug resistance invariably develops and switches these antiandrogens from antagonist to agonist of the AR. Accumulated evidence indicates that AR mutation is an important cause for the drug resistance. This review will give an overview of the mutation based resistance of the current clinically used antiandrogens and the rational drug design to overcome the resistance, provides a promising strategy for the development of the new generation of antiandrogens targeting HBP.
PubMed: 25852559
DOI: 10.3389/fphar.2015.00057