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1.
Nat Commun ; 11(1): 4822, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973149

RESUMO

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents.


Assuntos
Acetato de Abiraterona/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Verrucomicrobia/efeitos dos fármacos , Acetato de Abiraterona/metabolismo , Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Bactérias/metabolismo , Fezes/microbiologia , Humanos , Masculino , RNA Ribossômico 16S/genética , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Vitamina K 2/metabolismo , Vitamina K 2/farmacologia
2.
Nat Commun ; 11(1): 4498, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908142

RESUMO

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.


Assuntos
Macrófagos/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Biópsia , Buffy Coat/citologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimioterapia Adjuvante , Técnicas de Cocultura , Intervalo Livre de Doença , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Intervalo Livre de Progressão , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Procedimentos Cirúrgicos Robóticos , Transdução de Sinais/imunologia , Análise de Célula Única , Células THP-1 , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico
3.
Med Hypotheses ; 143: 110112, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721806

RESUMO

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/fisiologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/uso terapêutico , Antagonistas de Androgênios/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Indução Enzimática/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Obesidade/complicações , Obesidade/fisiopatologia , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Prognóstico , Receptores Virais/efeitos dos fármacos , Fatores de Risco , Serina Endopeptidases/efeitos dos fármacos , Distribuição por Sexo , Espironolactona/farmacologia , Internalização do Vírus/efeitos dos fármacos
4.
Prostate ; 80(12): 926-937, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542812

RESUMO

BACKGROUND: Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer. METHODS: To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days. RESULTS: Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner. CONCLUSIONS: Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Orquiectomia , Neoplasias da Próstata/cirurgia , Distribuição Aleatória , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Endocrinol ; 183(2): 181-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32454455

RESUMO

Objective: Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover. Design: Prospective cohort study. Methods: Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied. Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered. Conclusions: In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.


Assuntos
Antagonistas de Androgênios/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Acetato de Ciproterona/farmacologia , Adulto , Idoso , Bélgica , Remodelação Óssea/efeitos dos fármacos , Cálcio/sangue , Estudos de Coortes , Homeostase/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Estudos Prospectivos , Delitos Sexuais , Testosterona/sangue
7.
Nat Commun ; 11(1): 1613, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235862

RESUMO

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.


Assuntos
Antagonistas de Androgênios/farmacologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Testosterona/metabolismo , Antagonistas de Androgênios/uso terapêutico , Androgênios , Animais , Antineoplásicos/farmacologia , Medula Óssea/patologia , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Terapia de Reposição Hormonal/métodos , Pulmão/patologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Testosterona/imunologia
8.
Biomed Environ Sci ; 33(3): 158-164, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32209174

RESUMO

Objective: The purpose of this study was to investigate the anti-androgenic mechanism of cypermethrin involving coactivators. Methods: Mammalian two-hybrid assays were performed to study the effects of cypermethrin on interactions of the androgen receptor (AR) with the coactivators androgen receptor-associated protein 70 (ARA70) and androgen receptor-associated protein 55 (ARA55). Results: The results showed that AR-ARA70 and AR-ARA55 interactions were remarkably enhanced by dihydrotestosterone (DHT, P ≤ 0.05). Cypermethrin inhibited DHT-induced AR-ARA70 and AR-ARA55 interactions significantly ( P ≤ 0.05). Conclusion: The study indicates that cypermethrin exhibits inhibitory effects on AR transcription associated with repression of AR-ARA70 and AR-ARA55 interactions in a ligand-dependent manner. The data show novel anti-androgenic mechanisms of cypermethrin that contribute to male reproductive toxicology.


Assuntos
Antagonistas de Androgênios/farmacologia , Inseticidas/efeitos adversos , Piretrinas/efeitos adversos , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/efeitos adversos , Animais , Linhagem Celular , Chlorocebus aethiops , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Coativadores de Receptor Nuclear/metabolismo , Técnicas do Sistema de Duplo-Híbrido
9.
Prostate ; 80(2): 214-224, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31799745

RESUMO

BACKGROUND: Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. METHODS: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3 . Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. RESULTS: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. CONCLUSIONS: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.


Assuntos
Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Antagonistas de Androgênios/farmacologia , Androstenos/farmacologia , Animais , Antineoplásicos/farmacologia , Castração , Linhagem Celular Tumoral , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Isoformas de Proteínas , Receptores Androgênicos/genética , Taxoides/administração & dosagem , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Domest Anim Endocrinol ; 70: 106381, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479927

RESUMO

To study the long-term impact of neonatal exposure to endocrine-active compounds (EACs) on plasma lipid profiles, steroid concentrations, and morphology of porcine luteal tissue, piglets were injected with testosterone propionate (TP), flutamide (FLU), 4-tert-octylphenol, ICI 182,780 (ICI), methoxychlor, or corn oil (controls) between postnatal days 1 and 10 (n = 5/group). Blood samples and corpora lutea were obtained from sexually mature gilts. The investigated compounds differentially affected plasma lipid and steroid concentrations. Moreover, we demonstrated hypertrophy of luteal cells after neonatal EAC administration. In addition, a predominant abundance of lipid droplets was found in luteal cells of TP-, FLU-, and ICI-treated animals. It seems that the pathways leading to changes in the plasma lipid profile may contribute to the development of long-term alterations that have the potential to affect luteal steroidogenic capability in pigs.


Assuntos
Antagonistas de Androgênios/farmacologia , Hormônios/farmacologia , Suínos , Androgênios/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Hormônios/sangue , Inseticidas/farmacologia , Tensoativos/farmacologia
11.
Cancer Lett ; 473: 118-129, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31843555

RESUMO

Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography-mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.


Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias da Bexiga Urinária/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desacetilase 2/metabolismo , Humanos , Masculino , Fatores de Transcrição NFI/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Inibidor Secretado de Peptidases Leucocitárias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia
12.
J Antibiot (Tokyo) ; 73(1): 60-65, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481763

RESUMO

A norditerpenoid k4610422 (1), an inhibitor of testosterone-5α-reductase originally discovered from a mesophilic rare actinomycete of the genus Streptosporangium, was isolated from the culture extract of a thermophilic actinomycete Actinomadura sp. The complete 1H and 13C NMR assignment and absolute configuration of 1 were addressed by spectroscopic measurements including NOESY and CD spectra coupled with ECD calculation, which allowed to establish the (5 R,9 S,10 R,13 S)-configuration. Compound 1 was moderately cytotoxic against P388 murine leukemia cells with IC50 30 µM.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/efeitos dos fármacos , Actinomycetales/química , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Dicroísmo Circular , Diterpenos , Fermentação , Leucemia P388/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana
13.
Eur J Pharmacol ; 866: 172783, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31712062

RESUMO

The development of targeted therapies has been a consistent goal for hormone-related diseases treatment. As a result of increased knowledge of the role of androgens in different diseases, anti-androgen treatment is becoming increasingly important in targeted therapy. Androgens play an important role in different disorders, therefore, androgen receptor signalling is a crucial factor in pathological conditions. The androgen receptor is a transcription factor activated by the testosterone metabolite 5α-dihydrotestosterone and regulates the expression of genes related to sexual differentiation, growth and survival of prostate cells, and to a certain extent, cancer progression. Herein, we review anti-androgen therapies in cancer and other selected diseases and provide examples where anti-androgen drugs can be used as both main and supportive treatments in the multimodal therapeutic scheme. Even in diseases with low serum levels of testosterone or DHT, anti-androgen therapy plays an important role in new treatments. Therefore, the use of anti-androgens is an appealing strategy in which to overcome resistance to primary treatment by assuring better therapy results. In this review, we take into account both older generation hormonal drugs and the new drug classes. Additionally, we review recent studies that suggest new anti-androgen agents have not entirely replaced some of the old standards.


Assuntos
Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Terapia de Reposição Hormonal/métodos , Neoplasias/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Animais , Humanos
14.
Anim Reprod Sci ; 212: 106252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31864499

RESUMO

The current study was designed to gain insights into regulatory mechanisms mediating long-term effects of androgen excess or deficiency on corpus luteum function in pigs. Piglets were injected subcutaneously with testosterone propionate (TP, an androgen), flutamide (FLU, an anti-androgen) or corn oil (control) between postnatal Days 1 and 10. Corpora lutea from sexually mature gilts were examined for luteal steroid concentrations and processed for total RNA isolation and subsequent RNA sequencing to determine abundances of mRNA transcripts and microRNAs (miRNAs). Potential miRNA-mRNA interactions were explored in silico. Androstenedione, testosterone and estrone concentrations in corpora lutea were altered due to the disrupted androgen action in neonates. The luteal tissue had 465 and 353 genes for which there were differential mRNA abundances as compared with the control group (P-adjusted < 0.05; log2FC ≥ 1.0) in response to neonatal TP and FLU piglet treatments, respectively. Disruption of androgen signalling in neonates affected mRNA transcript abundance, as compared with the control group, for genes associated with apoptosis, angiogenesis and immune functions in the corpora lutea. Furthermore, there was a differential abundance of a group of miRNAs in the treatment groups compared with the control group. These results indicate the neonatal androgenic milieu affects the onset of luteolysis when these animals are sexually mature, although mechanisms for responses to TP or FLU likely differ. It is proposed that changes in specific miRNAs and mRNAs may, in part, account for long-term effects of androgen excess or androgen deficiency on corpus luteum function in pigs.


Assuntos
Corpo Lúteo/fisiologia , Flutamida/farmacologia , Maturidade Sexual/efeitos dos fármacos , Suínos/fisiologia , Propionato de Testosterona/farmacologia , Transcriptoma/fisiologia , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/farmacologia , Androgênios/administração & dosagem , Androgênios/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
15.
Physiol Rep ; 7(24): e14318, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31876126

RESUMO

Hypoxia is common with preterm birth and may lead to long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult-like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high-dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen-induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.


Assuntos
Antagonistas de Androgênios/farmacologia , Flutamida/farmacologia , Gônadas/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipóxia/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Gônadas/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Testosterona/sangue
16.
Cancer Treat Rev ; 81: 101871, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698174

RESUMO

Acquired resistance to a drug treatment is a common problem across many cancers including prostate cancer (PCa) - one of the major factors for male mortality. The androgen receptor (AR) continues to be the main therapeutic PCa target and despite the success of modern targeted therapies such as enzalutamide, resistance to these drugs eventually develops. The AR has found many ways to adapt to treatments including overexpression and production of functional, constitutively active splice variants. However, of particular importance are point mutations in the ligand binding domain of the protein that convert anti-androgens into potent AR agonists. This mechanism appears to be especially prevalent with the AR in spite of some distant similarities to other hormone nuclear receptors. Despite the AR being one of the most studied and attended targets in cancer, those gain-of-function mutations in the receptor remain a significant challenge for the development of PCa therapies. This drives the need to fully characterize such mutations and to consistently screen PCa patients for their occurrence to prevent adverse reactions to anti-androgen drugs. Novel treatments should also be developed to overcome this resistance mechanism and more attention should be given to the possibility of similar occurrences in other cancers.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/genética , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Terapia de Alvo Molecular , Mutação , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo
17.
Ginekol Pol ; 90(9): 520-526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588549

RESUMO

OBJECTIVES: Using anti-androgenic contraception is one of the methods of birth control. It also has a significant, non-contraceptiveimpact on women's body. These drugs can be used in various endocrinological disorders, because of their abilityto reduce the level of male hormones.The aim of our study is to establish a correlation between taking different types of anti-androgenic drugs and intensity ofhirsutism, acne, menstrual pain intensity and sexuality. MATERIAL AND METHODS: 570 women in childbearing age that had been using oral contraception for at least three monthstook part in our research. We examined women and asked them about quality of life, health, direct causes and effects ofthat treatment, intensity of acne and menstrual pain before and after. Our research group has been divided according tothe type of gestagen contained in the contraceptive pill: dienogest, cyproterone, chlormadynone and drospirenone. Additionally,the control group consisted of women taking oral contraceptives without antiandrogenic component. RESULTS: The mean age of the studied group was 23 years ± 3.23. 225 of 570 women complained of hirsutism.The mean score for acne intensity before the use of contraception was 2.7 ± 1.34. The mean score for acne intensity after3 months of using contraception was 1.85 ± 1.02 (p < 0.001). 192 women reported excess hairiness in one or more areabefore treatment. Mean value based on Ferriman-Gallway scale before the treatment was 6.23 ± 6.21 and 5.39 ± 5.6 afterthe treatment (p < 0.001). CONCLUSIONS: All groups of drugs effectively reduced pain and acne severity. Cyproterone and drospirenone turned outas the most effective drugs in treating hirsutism. Surprisingly, according to our research, dienogest does not have anyimpact on body hairiness.


Assuntos
Acne Vulgar , Antagonistas de Androgênios , Anticoncepcionais Orais , Dismenorreia , Hirsutismo , Acne Vulgar/tratamento farmacológico , Acne Vulgar/fisiopatologia , Adulto , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androstenos/farmacologia , Androstenos/uso terapêutico , Anticoncepcionais Orais/farmacologia , Anticoncepcionais Orais/uso terapêutico , Ciproterona/farmacologia , Ciproterona/uso terapêutico , Dismenorreia/tratamento farmacológico , Dismenorreia/fisiopatologia , Feminino , Hirsutismo/tratamento farmacológico , Hirsutismo/fisiopatologia , Humanos , Estudos Prospectivos , Qualidade de Vida , Sexualidade/efeitos dos fármacos , Adulto Jovem
18.
Oncol Rep ; 42(6): 2788-2796, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578588

RESUMO

Prostate cancer is closely associated with constitutive transactivation of the androgen receptor (AR) signaling pathway. After treatment with androgen­deprivation therapy (ADT), the majority of patients develop castration­resistant prostate cancer within months or years. In order to investigate potential novel therapeutic targets in addition to ADT, the present study examined the regulatory mechanisms of the AR signaling pathway. In the present study, LNCaP cells were metabolically­labeled with Alk­C16, a palmitate probe. In addition, cells were treated with R1881, an androgen, or DMSO. Subsequently, click­chemistry­based palmitoylome profiling was performed in LNCaP cells and palmitoylated proteins were compared between cells treated with androgen and untreated cells. Androgen treatment was revealed to significantly increase the palmitoylation level of α­tubulin. In addition, the palmitoylation level of Ras­related protein Rab­7a (Rab7a) was enhanced by androgen treatment. Palmitoylation of α­tubulin and Rab7a were essential for cell proliferation. Notably, in the supernatant of LNCaP cells, the palmitoylation level of α­tubulin was also increased following androgen treatment. Palmitoylation of α­tubulin may provide a new potential target for the treatment of prostate cancer. In addition, the high level of α­tubulin palmitoylation in the supernatant may represent a biomarker for early­stage prostate cancer.


Assuntos
Androgênios/genética , Neoplasias da Próstata/genética , Tubulina (Proteína)/genética , Proteínas rab de Ligação ao GTP/genética , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Lipoilação/genética , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteína S/genética , Proteína S/metabolismo , Transdução de Sinais/genética , Tubulina (Proteína)/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
19.
Biomed Pharmacother ; 120: 109490, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31574376

RESUMO

BACKGROUND: Emerging preclinical evidence suggests a critical role for androgen-mediated androgen receptor (AR) signaling in bladder cancer progression. However, researchers have not determined whether autophagy modulates the efficacy of an enzalutamide (ENZ) treatment in subjects with advanced bladder cancer. In this study, we investigated the synergistic effect of ENZ and autophagy inhibitors on bladder cancer. METHODS: ENZ was used as an anti-AR drug, and chloroquine (CQ), 3-methyladenine (3-MA), and bafilomycin A1 (BAF) were used as autophagy inhibitors. J82, T24, and UMUC3 cell lines were used as models of bladder cancer. A bifluorescence autophagy system with the mRFP-GFP-LC3 plasmid was used to evaluate autophagy flux. Protein and mRNA levels were detected using Western blotting and qPCR, respectively. A Cell Counting Kit-8 (CCK-8) assay, colony assay, and flow cytometry analysis were used to evaluate cell proliferation and apoptosis. Four-week-old BALB/c athymic nude mice were used in the in vivo assay. RESULTS: Based on the results obtained using the bifluorescence autophagy system, ENZ (10-20 µM) significantly facilitated the accumulation of autophagosomes and autolysosomes in the cytoplasm of J82 and T24 cells. Additionally, ENZ significantly increased the expression of autophagy-related genes (AMP-dependent protein kinase (AMPK), autophagy-related gene 5 (ATG5), microtubule-associated protein light chain 3B (LC3B), and UNC-51-like kinase 1 (ULK1)) and proteins (microtubule-associated protein 1 light chain 3-II/I (LC3-II/I), ATG5, and phosphorylated AMP-dependent protein kinase α (p-AMPKα)). The administration of ENZ monotherapy (10-20 µM) to J82 and T24 cells failed to alter proliferation and apoptosis. Concurrent treatment with ENZ and autophagy inhibitors distinctly triggered apoptosis and inhibited proliferation. Genetic inhibition of autophagy by specifically blocking ATG5 with siRNA also increased ENZ-induced apoptosis in J82 and T24 cells. In vivo, concurrent treatment with ENZ (25 mg/kg/day) and CQ (10 mg/kg/day) improved the therapeutic sensitivity by decreasing tumor growth and apoptosis. Additionally, overexpression of AR suppressed ENZ-induced autophagy-related genes (LC3-II/I, ATG5, and p-AMPKα) in T24 cells, and CQ exerted synergistic effects with ENZ to suppressed AR-responsive genes expression (KLK2 and KLK3) in bladder cancer. In UMUC3 cells, ENZ monotherapy directly induced anticancer effects, and concurrent treatment with ENZ and CQ also had a synergistic effect on proliferation and apoptosis. CONCLUSIONS: Autophagy may be a potential mechanism underlying ENZ-resistant bladder cancer. Blockade of autophagy significantly increased ENZ-induced apoptosis in bladder cancer. Thus, concurrent treatment with autophagy inhibitors and ENZ may be a novel therapeutic strategy for bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Feniltioidantoína/farmacologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo
20.
Cells ; 8(9)2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480771

RESUMO

While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.


Assuntos
Depressão/genética , Receptores Androgênicos/genética , Estresse Psicológico/genética , Antagonistas de Androgênios/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Depressão/etiologia , Feminino , Flutamida/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Receptores Androgênicos/deficiência , Estresse Psicológico/complicações
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