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1.
J Med Chem ; 64(3): 1570-1583, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523674

RESUMEN

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Andrógenos/toxicidad , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Receptores Androgénicos/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Med ; 27(2): 310-320, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33462444

RESUMEN

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.


Asunto(s)
Andrógenos/farmacología , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Receptores Androgénicos/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Femenino , Humanos , Células MCF-7 , Coactivador 3 de Receptor Nuclear/genética , Receptores Androgénicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
3.
Life Sci ; 259: 118208, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32763294

RESUMEN

Cancer is the second leading cause of death worldwide, with prostate cancer, the second most commonly diagnosed cancer among men. Prostate cancer develops in the peripheral zone of the prostate gland, and the initial progression largely depends on androgens, the male reproductive hormone that regulates the growth and development of the prostate gland and testis. The currently available treatments for androgen dependent prostate cancer are, however, effective for a limited period, where the patients show disease relapse, and develop androgen-independent prostate cancer (AIPC). Studies have shown various intricate cellular processes such as, deregulation in multiple biochemical and signaling pathways, intra-tumoral androgen synthesis; AR over-expression and mutations and AR activation via alternative growth pathways are involved in progression of AIPC. The currently approved treatment strategies target a single cellular protein or pathway, where the cells slowly develop resistance and adapt to proliferate via other cellular pathways over a period of time. Therefore, an increased research aims to understand the efficacy of combination therapy, which targets multiple interlinked pathways responsible for acquisition of resistance and survival. The combination therapy is also shown to enhance efficacy as well as reduce toxicity of the drugs. Thus, the present review focuses on the signaling pathways involved in the progression of AIPC, comprising a heterogeneous population of cells and the advantages of combination therapy. Several clinical and pre-clinical studies on a variety of combination treatments have shown beneficial outcomes, yet further research is needed to understand the potential of combination therapy and its diverse strategies.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Andrógenos/metabolismo , Terapia Combinada/métodos , Progresión de la Enfermedad , Quimioterapia Combinada/métodos , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Estudios Prospectivos , Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
4.
PLoS Pathog ; 16(7): e1008506, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32645119

RESUMEN

Circulating androgens can modulate immune cell activity, but the impact of androgens on viral pathogenesis remains unclear. Previous data demonstrate that testosterone reduces the severity of influenza A virus (IAV) infection in male mice by mitigating pulmonary inflammation rather than by affecting viral replication. To examine the immune responses mediated by testosterone to mitigate IAV-induced inflammation, adult male mice remained gonadally intact or were gonadectomized and treated with either placebo or androgen-filled (i.e., testosterone or dihydrotestosterone) capsules prior to sublethal IAV infection. Like intact males, treatment of gonadectomized males with androgens improved the outcome of IAV infection, which was not mediated by changes in the control of virus replication or pulmonary cytokine activity. Instead, androgens accelerated pulmonary leukocyte contraction to limit inflammation. To identify which immune cells were contracting in response to androgens, the composition of pulmonary cellular infiltrates was analyzed and revealed that androgens specifically accelerated the contraction of total pulmonary inflammatory monocytes during peak disease, as well as CD8+ T cells, IAV-specific CD8+ T numbers, cytokine production and degranulation by IAV-specific CD8+ T cells, and the influx of eosinophils into the lungs following clearance of IAV. Neither depletion of eosinophils nor adoptive transfer of CD8+ T cells could reverse the ability of testosterone to protect males against IAV suggesting these were secondary immunologic effects. The effects of testosterone on the contraction of immune cell numbers and activity were blocked by co-administration of the androgen receptor antagonist flutamide and mimicked by treatment with dihydrotestosterone, which was also able to reduce the severity of IAV in female mice. These data suggest that androgen receptor signaling creates a local pulmonary environment that promotes downregulation of detrimental inflammatory immune responses to protect against prolonged influenza disease.


Asunto(s)
Virus de la Influenza A/inmunología , Pulmón/efectos de los fármacos , Infecciones por Orthomyxoviridae/inmunología , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Animales , Femenino , Inflamación/inmunología , Inflamación/virología , Pulmón/inmunología , Masculino , Ratones Endogámicos C57BL , Ratas , Receptores Androgénicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología
5.
Medicine (Baltimore) ; 99(15): e19760, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32282738

RESUMEN

BACKGROUND: In recent years, metastatic castration-resistant prostate cancer (MCRPC) and studies related to MCRPC have drawn global attention. The main objective of this bibliometric study was to provide an overview of MCRPC, explore clusters and trends in research and investigate the future direction of MCRPC research. METHODS: A total of 4089 publications published between 1979 and 2018 were retrieved from the Web of Science (WoS) Core Collection database. Different aspects of MCRPC research, including the countries/territories, institutions, journals, authors, research areas, funding agencies and author keywords, were analyzed. RESULTS: The number of annual MCRPC publications increased rapidly after 2010. American researchers played a vital role in this increase, as they published the most publications. The most productive institution was Memorial Sloan Kettering Cancer Center. De Bono, JS (the United Kingdom [UK]) and Scher, HI (the United States of America [USA]) were the two most productive authors. The National Institutes of Health (NIH) funded the largest number of published papers. Analyses of keywords suggested that therapies (abiraterone, enzalutamide, etc.) would attract global attention after US Food and Drug Administration (FDA) approval. CONCLUSIONS: Developed countries, especially the USA, were the leading nations for MCRPC research because of their abundant funding and frequent international collaborations. Therapy was one of the most vital aspects of MCRPC research. Therapies targeting DNA repair or the androgen receptor (AR) signing pathway and new therapies especially prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) would be the next focus of MCRPC research.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/secundario , Publicaciones/normas , United States Food and Drug Administration/organización & administración , Androstenos/uso terapéutico , Bibliometría , Neoplasias Óseas/secundario , Reparación del ADN/efectos de los fármacos , Humanos , Masculino , Metástasis de la Neoplasia , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Publicaciones/tendencias , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/genética , Reino Unido/epidemiología , Estados Unidos/epidemiología
7.
Am J Physiol Renal Physiol ; 318(4): F922-F935, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32116019

RESUMEN

There are substantial sex differences in renal structure and ammonia metabolism that correlate with differences in expression of proteins involved in ammonia generation and transport. This study determined the role of testis-derived testosterone in these differences. We studied 4-mo-old male C57BL/6 mice 4 and 8 wk after either bilateral orchiectomy (ORCH) or sham-operated control surgery and determined the effect of testosterone replacement to reverse the effects of ORCH. Finally, we determined the cellular expression of androgen receptor (AR), testosterone's canonical target receptor. ORCH decreased kidney and proximal tubule size, and testosterone replacement reversed this effect. ORCH increased ammonia excretion in a testosterone-dependent fashion; this occurred despite similar food intake, which is the primary component of endogenous acid production. ORCH increased expression of both phosphoenolpyruvate, a major ammonia-generating protein, and Na+-K+-2Cl- cotransporter, which mediates thick ascending limb ammonia reabsorption; these changes were reversed with testosterone replacement. Orchiectomy also decreased expression of Na+/H+ exchanger isoform 3, which mediates proximal tubule ammonia secretion, in a testosterone-dependent pattern. Finally, ARs are expressed throughout the proximal tubule in both the male and female kidney. Testosterone, possibly acting through ARs, has dramatic effects on kidney and proximal tubule size and decreases ammonia excretion through its effects on several key proteins involved in ammonia metabolism.


Asunto(s)
Amoníaco/metabolismo , Terapia de Reemplazo de Hormonas , Riñón/efectos de los fármacos , Eliminación Renal/efectos de los fármacos , Testosterona/administración & dosificación , Animales , Femenino , Riñón/metabolismo , Masculino , Ratones Endogámicos C57BL , Orquiectomía , Fosfoenolpiruvato Carboxiquinasa (ATP)/genética , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Factores Sexuales , Simportadores de Sodio-Bicarbonato/genética , Simportadores de Sodio-Bicarbonato/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Miembro 1 de la Familia de Transportadores de Soluto 12/genética , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo , Testosterona/deficiencia
8.
J Urol ; 203(5): 940-948, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31845837

RESUMEN

PURPOSE: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown. MATERIALS AND METHODS: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials. RESULTS: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036). CONCLUSIONS: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.


Asunto(s)
Androstenodiona/farmacología , Castración/métodos , Recurrencia Local de Neoplasia/terapia , Neoplasias de la Próstata/terapia , Receptores Androgénicos/metabolismo , Testosterona/análogos & derivados , Testosterona/farmacología , Anabolizantes/farmacología , Andrógenos/farmacología , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Estudios de Seguimiento , Humanos , Masculino , Espectrometría de Masas , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estudios Prospectivos , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/efectos de los fármacos , Factores de Tiempo
9.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-31671779

RESUMEN

Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by increasing glycolysis, a hallmark in cancer initiation and development. In this study we evaluated the effect of androgen and Tip60 stimulus in AR pathway activation and HIF-1α stabilization, in terms of proliferation and cell metabolism in androgen-sensitive LNCaP cells. The protective role of the bioactive compounds sulforaphane and capsaicin against the effect of these stimuli leading to pro-carcinogenic features was also addressed. Sulforaphane and capsaicin decreased nuclear AR, prostate specific antigen and Bcl-XL levels, and cell proliferation induced by androgen and Tip60 in LNCaP cells. These bioactive compounds prevented the increase in glycolysis, hexokinase and pyruvate kinase activity, and reduced HIF-1α stabilization induced by androgen and Tip60 in LNCaP cells. The protective role of sulforaphane and capsaicin on prostate cancer may rely on mechanisms involving the inhibition of Tip60, AR and HIF-1α effects.


Asunto(s)
Andrógenos/metabolismo , Capsaicina/farmacología , Isotiocianatos/farmacología , Lisina Acetiltransferasa 5/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Capsaicina/química , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isotiocianatos/química , Lisina Acetiltransferasa 5/genética , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Piruvato Quinasa/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína bcl-X/metabolismo
10.
J Bioinform Comput Biol ; 17(5): 1950033, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31744364

RESUMEN

In this study, efforts are created to develop a quantitative structure-activity relationship (QSAR)-based model, which are used for the prediction of toxicities to reduce testing in animals, time, and money in the early stages of drug development. An efficient machine learning model is developed to predict the toxicity of those drug molecules which binds to the androgen receptor (AR). Toxicity prediction is performed in terms of their activity, activity score, potency, and efficacy by using various physicochemical properties. A multilevel ensemble model is proposed, where its first level is performed ensemble-based classification of activity, and the second level is performed ensemble-based regression of activity score, potency, and efficacy of only those drug molecules which have been found active during the classification level. The AR dataset has 10,273 drug molecules where 461 are active, and 9812 are inactive, and each drug molecule has 1444 features. Therefore, our dataset is highly imbalanced having a very large number of features. Initially, we performed feature selection then the class imbalance problem is resolved. The k-fold cross-validation is accomplished to measure the consistency of the model. Finally, our proposed multilevel ensemble model has been validated and compared with some existing models.


Asunto(s)
Relación Estructura-Actividad Cuantitativa , Receptores Androgénicos , Bibliotecas de Moléculas Pequeñas/toxicidad , Pruebas de Toxicidad/métodos , Simulación por Computador , Humanos , Modelos Lineales , Aprendizaje Automático , Redes Neurales de la Computación , Distribución Aleatoria , Receptores Androgénicos/efectos de los fármacos , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/química
11.
Int J Mol Sci ; 20(21)2019 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-31661769

RESUMEN

Previous studies demonstrated that the 52-kDa FK506-binding protein (FKBP52) proline-rich loop is functionally relevant in the regulation of steroid hormone receptor activity. While zebra fish (Danio rerio; Dr) FKBP52 contains all of the analogous domains and residues previously identified as critical for FKBP52 potentiation of receptor activity, it fails to potentiate activity. Thus, we used a cross-species comparative approach to assess the residues that are functionally critical for FKBP52 function. Random selection of gain-of-function DrFKBP52 mutants in Saccharomyces cerevisiae identified two critical residues, alanine 111 (A111) and threonine 157 (T157), for activation of receptor potentiation by DrFKBP52. In silico homology modeling suggests that alanine to valine substitution at position 111 in DrFKBP52 induces an open conformation of the proline-rich loop surface similar to that observed on human FKBP52, which may allow for sufficient surface area and increased hydrophobicity for interactions within the receptor-chaperone complex. A second mutation in the FKBP12-like domain 2 (FK2), threonine 157 to arginine (T157R), also enhanced potentiation, and the DrFKBP52-A111V/T157R double mutant potentiated receptor activity similar to human FKBP52. Collectively, these results confirm the functional importance of the FKBP52 proline-rich loop, suggest that an open conformation on the proline-rich loop surface is a predictor of activity, and highlight the importance of an additional residue within the FK2 domain.


Asunto(s)
Proteínas de Unión a Tacrolimus/química , Proteínas de Pez Cebra/química , Animales , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Mutación con Ganancia de Función , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Noqueados , Simulación de Dinámica Molecular , Dominios Proteicos Ricos en Prolina/genética , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transducción de Señal , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
12.
Int J Obes (Lond) ; 43(12): 2469-2479, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31455870

RESUMEN

BACKGROUND: Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. METHODS: Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. RESULTS: The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. CONCLUSIONS: Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC.


Asunto(s)
Diglicéridos , Hepatocitos/metabolismo , Lipogénesis/fisiología , Receptores Androgénicos , Animales , Células Cultivadas , Diglicéridos/metabolismo , Diglicéridos/farmacología , Femenino , Hígado/citología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo
13.
Molecules ; 24(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370197

RESUMEN

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR-coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure-activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound 14d that exhibited antiproliferative activity (IC50 value of 16 nM) on PCa cells. In addition, biochemical studies showed that 14d exerts its anticancer activity by inhibiting the AR-PELP1 interaction and AR transactivation.


Asunto(s)
Benzamidas/farmacología , Proteínas Co-Represoras/química , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/química , Factores de Transcripción/química , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas Co-Represoras/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Conformación Proteica en Hélice alfa/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Receptores Androgénicos/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/genética , Activación Transcripcional/efectos de los fármacos
14.
Prostate ; 79(14): 1597-1603, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31361358

RESUMEN

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies. METHODS: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory. RESULTS: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with 177 Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased. CONCLUSIONS: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.


Asunto(s)
Antígenos de Superficie/sangre , Glutamato Carboxipeptidasa II/sangre , Recurrencia Local de Neoplasia/terapia , Células Neoplásicas Circulantes/química , Neoplasias de la Próstata Resistentes a la Castración/terapia , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/terapia , Anciano , Anciano de 80 o más Años , Antígenos de Superficie/genética , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Dipéptidos/uso terapéutico , Glutamato Carboxipeptidasa II/genética , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Proyectos Piloto , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/genética , Neoplasias de la Próstata Resistentes a la Castración/sangre , ARN Mensajero/sangre , Receptores Androgénicos/efectos de los fármacos , Estudios Retrospectivos , Taxoides/uso terapéutico , Resultado del Tratamiento
15.
J Oncol Pharm Pract ; 25(8): 1968-1978, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31359832

RESUMEN

Apalutamide is a competitive inhibitor of the androgen receptor and binds directly to the ligand-binding domain. The US Food and Drug Administration approved apalutamide on 14 February 2018 for use in patients with nonmetastatic castration-resistant prostate cancer based upon results from the phase III SPARTAN trial demonstrating significantly longer metastasis-free survival over placebo. The SPARTAN trial evaluated 1207 patients with nonmetastatic castration-resistant prostate cancer who were randomized 2:1 to apalutamide or placebo in combination with androgen deprivation therapy. Patients who received apalutamide experienced statistically significantly longer metastasis-free survival (40.5 versus 16.2 months, hazard ratio 0.28 (95% confidence interval = 0.23-0.35); P < 0.0001), which was the major efficacy outcome. Rash, hypothyroidism, and fracture were reported to occur more frequently with apalutamide than placebo. Based upon these results, apalutamide was deemed a safe and effective treatment option for patients with nonmetastatic castration-resistant prostate cancer. Clinical trials are ongoing to expand its indication in the metastatic setting, and identify additional roles for apalutamide in the management of prostate cancer such as in the castrate-sensitive metastatic setting.


Asunto(s)
Antagonistas de Andrógenos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/administración & dosificación , Antagonistas de Andrógenos/efectos adversos , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Androgénicos/efectos de los fármacos , Resultado del Tratamiento
16.
Reprod Fertil Dev ; 31(11): 1719-1729, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31248476

RESUMEN

Finasteride is a drug that is widely used in the treatment of benign prostatic hyperplasia, hair loss and even as a chemotherapeutic agent in the treatment of prostatic adenocarcinoma. However, its use is known to cause several side effects in adults and it can also cause changes in the embryonic development of the male prostate, which is a cause for concern given the possibility of the accumulation of finasteride in the environment. Nevertheless, no studies have investigated the effects of finasteride on the development of the prostate in females, which occurs in several species of mammals. To evaluate the effects of intrauterine exposure to finasteride (500µgkg-1 day-1) on postnatal prostate development in the Mongolian gerbil in the present study, we used immunohistochemistry, immunofluorescence, serological analysis and three-dimensional reconstruction techniques. Differences were observed in the effects of finasteride on periductal smooth muscle and cell proliferation between the sexes, as well as intersex differences in the presence of the androgen receptor, which was elevated in males, and the oestrogen receptor ERα, which was increased in females. Together, the data indicate that the female prostate has its own hormone dynamics and that there are sex-specific differences in the way in which the female prostate reacts to prenatal exposure to finasteride.


Asunto(s)
Finasterida/farmacología , Gerbillinae/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Animales , Femenino , Inmunohistoquímica , Masculino , Organogénesis/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/veterinaria , Próstata/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Receptores Estrogénicos/efectos de los fármacos , Receptores Estrogénicos/metabolismo , Caracteres Sexuales
17.
Int J Exp Pathol ; 100(3): 192-201, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31131507

RESUMEN

Chrysin (5,7-dihydroxyflavone) is a bioactive compound found in different fruits, vegetables, honey and propolis. This flavone has been suggested for the treatment of reproductive dysfunction, mainly because of its antioxidant and hormonal properties. However, the effects of this polyphenol on the prostate are still poorly understood. The purpose of this study was to evaluate the effects of short-term chrysin exposure on the ventral male and female prostates of adult gerbils. To evaluate the androgenic potential of chrysin, gerbils were also exposed to testosterone. Male and female gerbils were exposed to chrysin (50 mg/kg/day, orally) or testosterone cypionate (1 mg/kg/week, subcutaneously) for 3, 7 and 21 days. Prostates were dissected for morphological, stereological and immunohistochemical analyses. Serum levels of testosterone and 17ß-estradiol were measured by ELISA. Serum testosterone levels were not increased by chrysin supplementation in males or females. However, only females treated with chrysin for 21 days showed an increase in estradiol levels. Increased androgen receptor immunoreactivity, higher proliferation rates and glandular hyperplasia were observed in male and female prostates for all chrysin treatment times. Additionally, increased oestrogen receptor alpha immunoreactivity was observed in all chrysin-treated females. Although chrysin and testosterone promoted similar morphological changes in the gerbil prostate, chrysin supplementation was less deleterious to prostate health, since it resulted in lower incidence of hyperplasia and an absence of neoplastic foci.


Asunto(s)
Flavonoides/farmacología , Efectos Tardíos de la Exposición Prenatal/patología , Próstata/efectos de los fármacos , Receptores Androgénicos/efectos de los fármacos , Animales , Disruptores Endocrinos/farmacología , Femenino , Gerbillinae , Masculino , Embarazo , Testosterona/análogos & derivados , Testosterona/farmacología , Factores de Tiempo
18.
Expert Opin Ther Pat ; 29(6): 439-453, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31092069

RESUMEN

INTRODUCTION: Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD). AREAS COVERED: The authors provide an overview of AR-modulating agents from 2012 to 2018. EXPERT OPINION: The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Desarrollo de Medicamentos , Descubrimiento de Drogas/métodos , Humanos , Masculino , Terapia Molecular Dirigida , Patentes como Asunto , Neoplasias de la Próstata/patología , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo
19.
Toxicol Appl Pharmacol ; 373: 26-38, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-31009690

RESUMEN

As the main toxic component of aristolochic acid, aristolochic acid I (AAI) is primarily found in Aristolochiaceae plants such as Aristolochia, Aristolochia fangchi and Caulis aristolochiae manshuriensis. AAI has been proven to be carcinogenic, mutagenic and nephrotoxic. Although the role of AAI in testicular toxicity has been reported, its mechanism of action is unknown. Using metabonomics and molecular biology techniques, we tried to identify the differential endogenous metabolites of AAI that may affect the changes in testicular function in mice, map the network of metabolic pathways, and systematically reveal the molecular mechanism of AAI-induced testicular toxicity. We found that AAI inhibited amino acid metabolism in mouse testicular cells, impeded the uptake and oxidative decomposition of fatty acids, prevented normal glucose uptake by testicular cells, which inhibited glycolysis and gluconeogenesis, affected the mitochondrial tricarboxylic acid (TCA) cycle, which impaired the ATP energy supply, decreased the number of spermatogenic cells and sperm in the testes, induced changes in the mitochondrial state of spermatogonial cells, and ultimately led to physiological and pathological changes in the testes. AAI also regulated the testicular physiological activity by regulating the androgen receptor and hormone levels. This study used metabonomics and other methods to elucidate the mechanism of AAI-induced testicular toxicity from a new angle.


Asunto(s)
Aminoácidos/metabolismo , Ácidos Aristolóquicos/toxicidad , Cromatografía Liquida , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Metabolómica/métodos , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Testículo/efectos de los fármacos , Animales , Ácidos Aristolóquicos/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Simulación del Acoplamiento Molecular , Oxidación-Reducción , Unión Proteica , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismo , Espermatogonias/patología , Testículo/metabolismo , Testículo/patología
20.
Eur Urol Focus ; 5(2): 147-154, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30772358

RESUMEN

CONTEXT: Recent studies focused on the molecular characterization of metastatic prostate cancer have identified genomic subsets and emerging resistance patterns. Detection of these alterations in patients has potential implications for therapy selection and prognostication. OBJECTIVE: The primary objective is to review the current landscape of clinical and molecular biomarkers in advanced prostate cancer and understand how they may reflect underlying tumor biology. We also discuss how these features may potentially impact earlier stages of the disease. EVIDENCE ACQUISITION: A literature search was performed of recent clinical biomarker/genomic studies focused on advanced metastatic prostate cancer as well as relevant preclinical studies investigating how these alterations influence therapy response or resistance. EVIDENCE SYNTHESIS: Metastatic castration-resistant prostate cancer is commonly driven by androgen receptor signaling even after progression on potent hormonal agents, but other alterations may also be present or emerge during therapy resistance such as DNA repair gene aberrations or combined loss of tumor suppressor genes. Biological implications of these changes are context dependent, which may affect their detection and interpretation. CONCLUSIONS: Molecular changes occur during prostate cancer progression and treatment resistance. Detection of genomic alterations has potential to influence therapy choice. Additional studies are warranted to elucidate the evolution of these changes and their impact in earlier stages of the disease. PATIENT SUMMARY: We review the biology of advanced prostate cancer, and highlight opportunities and challenges for using biological or molecular assays to help guide individualized treatment decisions for patients.


Asunto(s)
Biología Molecular/métodos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Antagonistas de Andrógenos/uso terapéutico , Biomarcadores/metabolismo , Progresión de la Enfermedad , Genómica/métodos , Humanos , Masculino , Metástasis de la Neoplasia/patología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/secundario , Receptores Androgénicos/efectos de los fármacos
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