-
Frontiers in Endocrinology 2023Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death in men. Androgen deprivation therapy (ADT) has become...
BACKGROUND
Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death in men. Androgen deprivation therapy (ADT) has become the first-line therapy for inhibiting PCa progression; however, nearly all patients receiving ADT eventually progress to castrate-resistant prostate cancer. Therefore, this study aimed to identify hub genes related to bicalutamide resistance in PCa and provide new insights into endocrine therapy resistance.
METHODS
The data were obtained from public databases. Weighted correlation network analysis was used to identify the gene modules related to bicalutamide resistance, and the relationship between the samples and disease-free survival was analyzed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed, and hub genes were identified. The LASSO algorithm was used to develop a bicalutamide resistance prognostic model in patients with PCa, which was then verified. Finally, we analyzed the tumor mutational heterogeneity and immune microenvironment in both groups.
RESULTS
Two drug resistance gene modules were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that both modules are involved in RNA splicing. The protein-protein interaction network identified 10 hub genes in the brown module , , , , , , , , , and ) and 13 in the yellow module (, , , , , , , , , , , , and ). The prognostic model composed of , , , , , , , , , , , and could effectively predict patient prognosis. Genomic analysis revealed that the high- and low-risk groups had different mutation maps. Immune infiltration analysis showed a statistically significant difference in immune infiltration between the high- and low-risk groups, and that the high-risk group may benefit from immunotherapy.
CONCLUSION
In this study, bicalutamide resistance genes and hub genes were identified in PCa, a risk model for predicting the prognosis of patients with PCa was constructed, and the tumor mutation heterogeneity and immune infiltration in high- and low-risk groups were analyzed. These findings offer new insights into ADT resistance targets and prognostic prediction in patients with PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Prognosis; Anilides; Tumor Microenvironment; Repressor Proteins; Trans-Activators; Vacuolar Proton-Translocating ATPases; Nuclear Proteins
PubMed: 37143720
DOI: 10.3389/fendo.2023.1125299 -
Scientific Reports Nov 2023Acne vulgaris, a prevalent skin disorder among teenagers and young adults, can have numerous psychological consequences. Topical treatment of acne would be advantageous...
Acne vulgaris, a prevalent skin disorder among teenagers and young adults, can have numerous psychological consequences. Topical treatment of acne would be advantageous by reducing the risk of systemic adverse drug reactions. However, the major challenge would be skin penetration through the stratum corneum. Therefore, during this study, tretinoin (TRT) and bicalutamide (BCT) loaded niosomes with follicular targeting potential were fabricated through the thin film hydration technique. Formulation optimization was performed using the Design-Expert software and optimum formulation was characterized in terms of particle size, zeta potential, transmission electron microscopy, drug loading, and differential scanning calorimetry. In vivo follicular targeting was assessed using rhodamine B-loaded niosomes to follow the skin penetration pathways. The results showed that, the optimum formulation was spherical in shape and had an average diameter of 319.20 ± 18.50 nm and a zeta potential of - 29.70 ± 0.36 mV. Furthermore, entrapment efficiencies were 94.63 ± 0.50% and > 99% and loading capacities were 1.40 ± 0.01% and 1.48 ± 0.00% for BCT and TRT, respectively. According to the animal study results, the prepared niosomes with an average diameter of about 300 nm showed significant accumulation in hair follicles. It seems that the designed niosomal BCT-TRT co-delivery system would be promising in acne management with follicular targeting potential.
Topics: Animals; Liposomes; Skin Absorption; Tretinoin; Acne Vulgaris; Particle Size
PubMed: 37973805
DOI: 10.1038/s41598-023-47302-6 -
Computational Biology and Chemistry Jun 2021There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart...
There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 μM dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.
Topics: Androgen Receptor Antagonists; Humans; Ligands; Models, Molecular; Receptors, Androgen; Tumor Cells, Cultured
PubMed: 33932781
DOI: 10.1016/j.compbiolchem.2021.107490 -
Cancers Dec 2022Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low... (Review)
Review
Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low overall survival rate, and an unexplored therapeutic approach. Although the basal subtype transcends the group and contributes approximately 80% to triple-negative breast cancer (TNBC) cases, the exceptionally appearing mesenchymal and luminal androgen receptor (LAR) subtypes portray an unfathomable clinical course. LAR with a distinct generic profile frequently metastasizes to regional lymph nodes and bones. This subtype is minimally affected by chemotherapy and shows the lowest pathologic complete response. The androgen receptor is the only sex steroid receptor that plays a cardinal role in the progression of breast cancers and is typically overexpressed in LAR. The partial AR antagonist bicalutamide and the next-generation AR inhibitor enzalutamide are being assessed in standard protocols for the mitigation of TNBC. There arises an inevitable need to probe into the strategies that could neutralize these androgen receptors and alleviate the trajectory of concerning cancer. This paper thus focuses on reviewing literature that provides insights into the anti-androgenic elements against LAR typical TNBC that could pave the way for clinical advancements in this dynamic sphere of oncology.
PubMed: 36612226
DOI: 10.3390/cancers15010233 -
Cell Communication and Signaling : CCS Nov 2022Bicalutamide is a nonsteroidal antiandrogen widely used as a first-line clinical treatment for advanced prostate cancer (PCa). Although patients initially show effective...
BACKGROUND
Bicalutamide is a nonsteroidal antiandrogen widely used as a first-line clinical treatment for advanced prostate cancer (PCa). Although patients initially show effective responses to bicalutamide treatment, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa (CRPC). This research investigated the roles of the oestrogen receptor α (ERα)-nuclear factor E2-related factor 2 (NRF2) signalling pathway in bicalutamide resistance in PCa cells.
METHODS
We performed bioinformatic analysis and immunohistochemical staining on normal and cancerous prostate tissue to evaluate ERα and NRF2 expression and their correlation. Gene expression and localization in PCa cell lines were further investigated using real-time reverse transcription PCR/Western blotting and immunofluorescence staining. We treated PCa cells with the ER inhibitor tamoxifen and performed luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays to understand ERα-dependent NRF2 expression. Overexpression and knockdown of ERα and NRF2 were used to explore the potential role of the ERα-NRF2 signalling axis in bicalutamide resistance in PCa cells.
RESULTS
We found that the expression of ERα and NRF2 was positively correlated and was higher in human CRPC tissues than in primary PCa tissues. Treatment with oestrogen or bicalutamide increased the expression of ERα and NRF2 as well as NRF2 target genes in PCa cell lines. These effects were blocked by pretreatment with tamoxifen. ChIP assays demonstrated that ERα directly binds to the oestrogen response element (ERE) in the NRF2 promoter. This binding led to increased transcriptional activity of NRF2 in a luciferase reporter assay. Activation of the ERα-NRF2 signalling axis increased the expression of bicalutamide resistance-related genes. Inhibition of this signalling axis by knockdown of ERα or NRF2 downregulated the expression of bicalutamide resistance-related genes and inhibited the proliferation and migration of PCa cells.
CONCLUSIONS
We demonstrated the transcriptional interaction between ERα and NRF2 in CRPC tissues and cell lines by showing the direct binding of ERα to the ERE in the NRF2 promoter under oestrogen treatment. Activation of the ERα-NRF2 signalling axis contributes to bicalutamide resistance in PCa cells, suggesting that the ERα-NRF2 signalling axis is a potential therapeutic target for CRPC. Video Abstract.
Topics: Humans; Male; Cell Line, Tumor; Estrogen Receptor alpha; Estrogens; Gene Expression Regulation, Neoplastic; NF-E2-Related Factor 2; Prostatic Neoplasms, Castration-Resistant; Tamoxifen
PubMed: 36376959
DOI: 10.1186/s12964-022-00979-0 -
PloS One 2015Gynecomastia and/or mastodynia is a common medical problem in patients receiving antiandrogen (bicalutamide or flutamide) treatment for prostate cancer; up to 70% of... (Review)
Review
INTRODUCTION
Gynecomastia and/or mastodynia is a common medical problem in patients receiving antiandrogen (bicalutamide or flutamide) treatment for prostate cancer; up to 70% of these patients result to be affected; furthermore, this can jeopardise patients' quality of life.
AIMS
To systematically review the quality of evidence of the current literature regarding treatment options for bicalutamide-induced gynecomastia, including efficacy, safety and patients' quality of life.
METHODS
The PubMed, Medline, Scopus, The Cochrane Library and SveMed+ databases were systematically searched between January 1, 2000 and December 31, 2014. All searches were undertaken between January and February 2015. The search phrase used was:"gynecomastia AND treatment AND prostate cancer". Two reviewers assessed 762 titles and abstracts identified. The search and review process was done in accordance with the PRISMA statement. The PICOS (patients, intervention, comparator, outcomes and study design) process was used to specify inclusion criteria. Quality of evidence was rated according to GRADE.
MAIN OUTCOME MEASURES
Primary outcomes were: treatment effects, number of complications and side effects. Secondary outcome was: Quality of Life.
RESULTS
Eleven studies met the inclusion criteria and are analysed in this review. Five studies reported pharmacological intervention with tamoxifen and/or anastrozole, either as prophylactic or therapeutic treatment. Four studies reported radiotherapy as prophylactic and/or therapeutic treatment. Two studies compared pharmacological treatment to radiotherapy. Most of the studies were randomized with varying risk of bias. According to GRADE, quality of evidence was moderate to high.
CONCLUSIONS
Bicalutamide-induced gynecomastia and/or mastodynia can effectively be managed by oral tamoxifen (10-20 mg daily) or radiotherapy without relevant side effects. Prophylaxis or therapeutic treatment with tamoxifen results to be more effective than radiotherapy.
Topics: Androgen Antagonists; Gynecomastia; Humans; Male; Meta-Analysis as Topic; Prostatic Neoplasms; Quality of Life
PubMed: 26308532
DOI: 10.1371/journal.pone.0136094 -
Current Molecular Biology Reports 2017Compensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in... (Review)
Review
PURPOSE OF REVIEW
Compensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous.
RESEARCH FINDINGS
As with other anti-androgens, these mechanisms include alterations of AR but also may be associated with overexpression of oncogenes which should be targeted by novel therapies. Androgen receptor splice variants have been frequently described in patients who developed enzalutamide resistance. Mutant AR F876L has been detected in patients who are resistant to enzalutamide. Glucocorticoid receptor overexpression has been observed in patient tissues and in pre-clinical models of enzalutamide resistance.
SUMMARY
There is a heterogeneous picture of enzalutamide resistance in prostate cancer and, therefore, the development of appropriate post-enzalutamide treatment remains a challenge.
PubMed: 29214142
DOI: 10.1007/s40610-017-0079-1 -
Frontiers in Endocrinology 2023Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC). There is a lack of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC). There is a lack of direct comparison of the therapeutic effects and adverse events between the conventional ARI (bicalutamide) and three second-generation ARIs (enzalutamide, apalutamide and darolutamide).
METHODS
Our network meta-analysis evaluated therapeutic effects and adverse events of the conventional ARI (bicalutamide) and the second-generation ARIs in treating CRPC. We systematically searched the Pubmed, Cochrane library and Embase databases for studies published until October 2022 and only randomized clinical trials (RCTs) were included. The progression-free survival, prostate-specific antigen (PSA) progression-free survival, overall survival (PFS/PSA-PFS/OS), PSA response rate and relative adverse events (AEs) of CRPC patients were collected and synthesized. We then performed subgroup analysis. The non-metastatic and metastatic CRPC (nm/mCRPC) observations were analyzed separately. Data analyses were performed using R software (4.2.1) based on Bayesian framework.
RESULTS
6,993 subjects from seven eligible RCTs were analyzed. Enzalutamide, apalutamide and darolutamide were more effective than bicalutamide in treating CRPC, and the performance of darolutamide was slightly worse than the other two second-generation ARIs. Similar adverse events rate were observed among the second-generation ARIs and bicalutamide. Apalutamide showed a slightly higher rate of Grade 3+ AEs, percentages of AE-related drug withdrawals and AE-related mortality. Patients receiving enzalutamide had significantly higher rate of hypertension and fatigue. In subgroup analysis, enzalutamide showed better therapeutic effects compared with bicalutamide in both nmCRPC and mCRPC groups. In nmCRPC group, enzalutamide and apalutamide had more benefits on PFS and PSA-PFS compared with darolutamide. We displayed the probability ranking map of PFS, PSA-PFS, OS, time to cytotoxic chemotherapy, PSA response rate and relative AE outcomes.
CONCLUSION
The current network meta-analysis indicated that the second-generation ARIs were superior to the conventional ARI, bicalutamide. The three second-generation ARIs showed incomplete equivalence on CRPC treatment. The darolutamide was slightly less effective compared with enzalutamide and apalutamide. The adverse events of apalutamide were worse than the others, but no statistical significance was observed among these vital AEs. All ARIs were generally well-tolerated. These results may provide reference to clinical decision and further direct comparison trials.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022370842.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Prostate-Specific Antigen; Network Meta-Analysis; Treatment Outcome; Androgen Receptor Antagonists
PubMed: 36843606
DOI: 10.3389/fendo.2023.1131033 -
Journal of Nuclear Medicine : Official... Aug 2022A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited...
A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited efficacy, with about a 19% clinical benefit rate. We investigated the therapeutic enhancement of antiandrogens as radiosensitizers in combination with F-FDG in TNBC. We screened 5 candidate drugs to evaluate shared toxicity when combined with either F-FDG, x-rays, or ultraviolet radiation, at doses below their respective half-maximal inhibitory concentrations. Cytotoxic enhancement of antiandrogen in combination with F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, the therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Bicalutamide, an antiandrogen drug, was found to share similar toxicity in combination with either F-FDG or x-rays, indicating its sensitivity as a radiosensitizer to F-FDG. Cell proliferation assays demonstrated selective toxicity of combination bicalutamide-F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation-induced damage to cells, suggesting the role of bicalutamide as a radiosensitizer to F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1, and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of bicalutamide and F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathologic examination corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. These data provide evidence that F-FDG in conjunction with antiandrogens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.
Topics: Androgen Antagonists; Animals; Cell Line, Tumor; Fluorodeoxyglucose F18; Humans; Mice; Nitriles; Radiation-Sensitizing Agents; Receptors, Androgen; Triple Negative Breast Neoplasms; Ultraviolet Rays
PubMed: 34772792
DOI: 10.2967/jnumed.121.262958 -
Current Problems in Cancer 2016Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast... (Review)
Review
Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer.
Topics: Androgen Antagonists; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Receptors, Androgen; Triple Negative Breast Neoplasms
PubMed: 27816190
DOI: 10.1016/j.currproblcancer.2016.09.004