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Medicine Apr 2020Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer... (Observational Study)
Observational Study
Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 μmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.
Topics: Adult; Anilides; Cell Proliferation; Dose-Response Relationship, Drug; Female; Flow Cytometry; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nitriles; Tetrazolium Salts; Tosyl Compounds; Triple Negative Breast Neoplasms
PubMed: 32332626
DOI: 10.1097/MD.0000000000019822 -
Experimental Biology and Medicine... Jun 2018Prostate cancer is the most common cancer in men, and before it progresses and metastasizes, the anticancer drug bicalutamide is often administered to patients. Many...
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. Based on the results, 314 proteins were differentially expressed between the LNCaP and LNCaP treated with bicalutamide. The apoptosis pathway associated with differentially expressed proteins was shown in the Kyoto Encyclopedia of Gene and Genome pathway mapper. The Kyoto Encyclopedia of Gene and Genome pathway mapper results revealed that the fodrin-mediated apoptosis pathway is associated with the actions of bicalutamide and Western blotting was performed to validate these results. Impact statement We studied bicalutamide's anticancer action by using proteomics. The effect of bicalutamide on androgen-exposed LNCaP cells was also studied. KEGG identified >1.8-fold differentially expressed proteins between test group cells. KEGG mapper showed fodrin-mediated apoptosis involvement in bicalutamide's action. The anticancer effects of bicalutamide, which was further confirmed using Western blotting. Therefore, this drug is a potential candidate for understanding bicalutamide's effect on LNCaP and fodrin can be used as a biomarker monitoring status in metastatic carcinoma.
Topics: Anilides; Antineoplastic Agents; Apoptosis; Calpain; Carrier Proteins; Cell Line, Tumor; Humans; Male; Microfilament Proteins; Models, Biological; Nitriles; Prostatic Neoplasms; Tosyl Compounds
PubMed: 29860890
DOI: 10.1177/1535370218779780 -
Cell Communication and Signaling : CCS Mar 2022Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a...
BACKGROUND
Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17β-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear.
METHODS
To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter.
RESULTS
CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1 PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter.
CONCLUSIONS
Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Video Abstract.
Topics: Androgen Antagonists; Androgens; Castration; Catalysis; Cell Line, Tumor; Cytochrome P-450 CYP1B1; Estradiol; Estrogen Receptor alpha; Humans; Interleukin-6; Male; Neoplastic Stem Cells; Prostate; Prostatic Neoplasms, Castration-Resistant
PubMed: 35292057
DOI: 10.1186/s12964-021-00807-x -
Pharmaceutics May 2020The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although...
The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone--vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively.
PubMed: 32397432
DOI: 10.3390/pharmaceutics12050438 -
International Journal of Trichology 2023Bicalutamide is a selective androgen receptor antagonist. To date, it has been used orally with good efficacy results, but not in mesotherapy. In our center, we assessed...
Bicalutamide is a selective androgen receptor antagonist. To date, it has been used orally with good efficacy results, but not in mesotherapy. In our center, we assessed whether patients undergoing bicalutamide mesotherapy showed positive responses and tolerated the local administration of bicalutamide. Six premenopausal women, with a mean age of 35.7 years and clinical diagnosis of Olsen Grade II or III female androgenetic alopecia accompanied by significant seborrhea were treated with 1 ml bicalutamide 0.5% mesotherapy. Three monthly sessions were performed. A subtle improvement in hair density was described after the third session. The overall satisfaction of the patients with the treatment was 6.3, on a scale of 1-10. Premenopausal women require several therapeutic approaches to combat severe androgenetic alopecia. Our data showed that bicalutamide mesotherapy was well tolerated and welcomed by the patients; we, therefore, provide a new tool for the management of this pathology.
PubMed: 37305191
DOI: 10.4103/ijt.ijt_78_21 -
Cell Communication and Signaling : CCS Sep 2023Adipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an...
BACKGROUND
Adipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an essential player in prostate cancer progression. Since obesity is directly related to human tumor progression, and adipose tissue depots are one of the significant components of the tumor microenvironment, the molecular mediators of the communication between adipocytes and epithelial cells are in the spotlight. Although periprostatic white adipose tissue contributes to prostate cancer progression, brown adipose tissue (BAT), which has beneficial effects in metabolic pathologies, has been scarcely investigated concerning cancer progression. Given that adipose tissue is a target of androgen signaling, the actual role of androgen removal on the periprostatic adipose tissue was the aim of this work.
METHODS
Surgical castration of the transgenic adenocarcinoma of the mouse prostate (TRAMP) was employed. By histology examination and software analysis, WAT and BAT tissue was quantified. 3T3-like adipocytes were used to study the role of Casodex® in modifying adipocyte differentiation and to investigate the function of the secretome of adipocytes on the proliferation of androgen-dependent and independent prostate cancer cells. Finally, the role of cell communication was assayed by TRAMP-C1 xenograft implanted in the presence of 3T3-like adipocytes.
RESULTS
Androgen removal increases brown/beige adipose tissue in the fat immediately surrounding the prostate glands of TRAMP mice, concomitant with an adjustment of the metabolism. Castration increases body temperature, respiratory exchange rate, and energy expenditure. Also, in vitro, it is described that blocking androgen signaling by Casodex® increases the uncoupling protein 1 (UCP1) marker in 3T3-like adipocytes. Finally, the effect of brown/beige adipocyte secretome was studied on the proliferation of prostate cancer cells in vivo and in vitro. The secretome of brown/beige adipocytes reduces the proliferation of prostate cancer cells mediated partly by the secretion of extracellular vesicles.
CONCLUSIONS
Consequently, we concluded that hampering androgen signaling plays a crucial role in the browning of the periprostatic adipose tissue. Also, the presence of brown adipocytes exhibits the opposite effect to that of white adipocytes in vitro regulating processes that govern the mechanisms of cell proliferation of prostate cancer cells. And finally, promoting the browning of adipose tissue in the periprostatic adipose tissue might be a way to handle prostate cancer cell progression. Video Abstract.
Topics: Male; Humans; Mice; Animals; Prostate; Androgens; Tumor Microenvironment; Castration; Prostatic Neoplasms
PubMed: 37770940
DOI: 10.1186/s12964-023-01294-y -
Prostate International Sep 2023Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen...
BACKGROUND
Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents.
MATERIALS AND METHODS
We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate.
RESULTS
We identified 18 RCTs ( = 13,509). Concerning OS, ADT + abiraterone, ADT + abiraterone + docetaxel, ADT + apalutamide, ADT + bicalutamide, ADT + darolutamide + docetaxel, ADT + enzalutamide, ADT + orteronel, and ADT + rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT + bicalutamide, nilutamide, flutamide, ADT + bicalutamide + palbociclib, and ADT + nilutamide. ADT + docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis.
CONCLUSIONS
Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT + docetaxel SOC. Even so, ADT + docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.
PubMed: 37745904
DOI: 10.1016/j.prnil.2023.06.003 -
Pharmaceutics Mar 2022The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous...
The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15−313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van’t Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability.
PubMed: 35336047
DOI: 10.3390/pharmaceutics14030674 -
Scientific Reports Jan 2024The objective of this study is to compare the efficacy of apalutamide and bicalutamide in combination with androgen deprivation therapy in patients with metastatic...
The objective of this study is to compare the efficacy of apalutamide and bicalutamide in combination with androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We retrospectively collected the data of about 330 patients with metastatic hormone-sensitive prostate cancer at our hospital and affiliated hospitals between December 2013 and August 2023. Sixty-one patients were administered apalutamide (240 mg/day) with androgen deprivation therapy (group A), and 269 patients were administered bicalutamide (80 mg/day) with androgen deprivation therapy (group B). Propensity score matching was used to adjust for clinical background factors between the two groups. PSA progression-free survival and overall survival were significantly longer in group A than in group B among the matched patients. Apalutamide therapy was a significant independent factor for OS in matched patients. The second progression-free survival of group A was significantly longer than that of group B in matched patients. Patients treated with apalutamide achieved ≥ 90% PSA decline from baseline faster and in larger numbers than those with bicalutamide. Apalutamide combined with ADT may be superior to bicalutamide alone in terms of OS and PSA-PFS in patients with mHSPC.
Topics: Male; Humans; Androgen Antagonists; Androgens; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies
PubMed: 38184704
DOI: 10.1038/s41598-024-51389-w -
Oncology Reports Jan 2022Androgen deprivation therapy (ADT) is used to treat prostate cancer (PCa). However, ADT may increase the expression of androgen receptor () through the amplification of...
Androgen deprivation therapy (ADT) is used to treat prostate cancer (PCa). However, ADT may increase the expression of androgen receptor () through the amplification of chromosome X. The gene oligophrenin 1 () is located in the same region as the gene, which could be amplified by ADT. Thus, the role of in PCa pathology was investigated. The expression status of in PCa was searched in The Cancer Genome Atlas (TCGA) database. Androgen‑sensitive cells LNCaP and 22RV1 were cultured under ADT conditions, and then the expression of was evaluated by northern blotting. The expression of was enhanced or knocked down in LNCaP and 22RV1 cells by transfection. Subsequently, the LNCaP and 22RV1 cells were cultured under ADT, and the viability rate, apoptosis, and migration of cells were assessed by MTT, flow cytometry, and Transwell assay respectively. The expression of was also enhanced or knocked down in androgen‑insensitive PC3 cells, and then the effects of OPHN1 on the viability, apoptosis, and migration of PC3 cells were assessed. A mouse xenograft model was created by injecting LNCaP cells with overexpression subcutaneously, and the tumor growth rates were monitored. In TCGA database, amplification of the gene was observed in the PCa tumors. ADT increased the expression of in LNCaP and 22RV1 cells (P<0.05). could promote resistance of LNCaP and 22RV1 cells to ADT by promoting cell survival and preventing their apoptosis (P<0.05). In addition, contributed to cell viability (P<0.05) and enhanced the migration ability in LNCaP, 22RV1 and PC3 cells (P<0.05). In the mouse model, the PCa xenograft with overexpression had a higher growth rate and was more resistant to the ADT condition (P<0.05). In summary, ADT induced the overexpression of in PCa, which facilitated PCa cell survival and promoted PCa progression.
Topics: Androgen Antagonists; Anilides; Animals; Apoptosis; Cytoskeletal Proteins; GTPase-Activating Proteins; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Nitriles; Nuclear Proteins; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Tosyl Compounds
PubMed: 34738630
DOI: 10.3892/or.2021.8214