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1.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672769

RESUMEN

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Proteolisis/efectos de los fármacos
2.
Cell Transplant ; 30: 963689721991477, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33522308

RESUMEN

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/complicaciones , Antagonistas de Estrógenos/uso terapéutico , Neoplasias de la Próstata/complicaciones , Tamoxifeno/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , /metabolismo , Descubrimiento de Drogas , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/análisis , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/análisis , Serina Endopeptidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacología
3.
Nat Commun ; 12(1): 401, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33452241

RESUMEN

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.


Asunto(s)
Carcinogénesis/genética , Criptocromos/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación/genética , Anciano , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Andrógenos/metabolismo , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Criptocromos/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Estudios de Seguimiento , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , RNA-Seq , Receptores Androgénicos/metabolismo , Reparación del ADN por Recombinación/efectos de los fármacos , Estudios Retrospectivos
4.
J Med Chem ; 64(2): 909-924, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33470111

RESUMEN

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Biotransformación , Línea Celular Tumoral , Perros , Descubrimiento de Drogas , Resistencia a Antineoplásicos/genética , Hepatocitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Ratas , Relación Estructura-Actividad
5.
Chemosphere ; 262: 128313, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33182081

RESUMEN

Androgens and androgen receptor regulate a variety of biological effects in the human body. The impaired functioning of androgen receptor may have different adverse health effects from cancer to infertility. Therefore, it is important to determine whether new chemicals have any binding activity and act as androgen agonists or antagonists before commercial use. Due to the large number of chemicals that require experimental testing, the computational methods are a viable alternative. Therefore, the aim of the present study was to develop predictive QSAR models for classifying compounds according to their activity at the androgen receptor. A large data set of chemicals from the CoMPARA project was used for this purpose and random forest classification models have been developed for androgen binding, agonistic, and antagonistic activity. In addition, a unique effort has been made for multi-class approach that discriminates between inactive compounds, agonists and antagonists simultaneously. For the evaluation set, the classification models predicted agonists with 80% of accuracy and for the antagonists' and binders' the respective metrics were 72% and 78%. Combining agonists, antagonists and inactive compounds into a multi-class approach added complexity to the modelling task and resulted to 64% prediction accuracy for the evaluation set. Considering the size of the training data sets and their imbalance, the achieved evaluation accuracy is very good. The final classification models are available for exploring and predicting at QsarDB repository (https://doi.org/10.15152/QDB.236).


Asunto(s)
Antagonistas de Receptores Androgénicos/clasificación , Andrógenos/clasificación , Modelos Químicos , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos/química , Andrógenos/farmacología , Humanos , Aprendizaje Automático , Unión Proteica , Relación Estructura-Actividad Cuantitativa
6.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33339129

RESUMEN

Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.


Asunto(s)
Andrógenos/deficiencia , Redes Reguladoras de Genes , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/genética , Transcriptoma , Antagonistas de Receptores Androgénicos/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Células Madre Neoplásicas/metabolismo , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología
7.
Anesthesiology ; 133(4): 852-866, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32930727

RESUMEN

BACKGROUND: Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. METHODS: Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). RESULTS: Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). CONCLUSIONS: Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.


Asunto(s)
Anestésicos por Inhalación/toxicidad , Isoflurano/toxicidad , Receptores Androgénicos/fisiología , Miembro 2 de la Familia de Transportadores de Soluto 12/fisiología , Factores de Edad , Antagonistas de Receptores Androgénicos/farmacología , Animales , Animales Recién Nacidos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Sprague-Dawley , Factores Sexuales
8.
Nat Genet ; 52(10): 1011-1017, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32868907

RESUMEN

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.


Asunto(s)
Factor Nuclear 3-alfa del Hepatocito/genética , Histona Demetilasas/genética , Neoplasias de la Próstata/genética , Unión Proteica/genética , Antagonistas de Receptores Androgénicos/farmacología , Animales , Línea Celular Tumoral , Cromatina/genética , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Hormonas Esteroides Gonadales/genética , Xenoinjertos , Humanos , Masculino , Ratones , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética
9.
Prostate ; 80(11): 885-894, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32483877

RESUMEN

BACKGROUND: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. METHODS: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. RESULTS: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. CONCLUSIONS: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Andrógenos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Línea Celular Tumoral , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Masculino , Células PC-3 , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo
10.
Prostate ; 80(12): 993-1005, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32559345

RESUMEN

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance. METHODS: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models. RESULTS: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice. CONCLUSIONS: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.


Asunto(s)
Piperidinas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata Resistentes a la Castración/patología , Distribución Aleatoria , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/metabolismo , Survivin/antagonistas & inhibidores , Survivin/biosíntesis , Ubiquitinación , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Chemosphere ; 257: 127178, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32505947

RESUMEN

Hydraulic fracturing (HF) technology is increasingly utilized for oil and gas extraction operations. The widespread use of HF has led to concerns of negative impacts on both the environment and human health. Indeed, the potential endocrine disrupting impacts of HF chemicals is one such knowledge gap. Herein, we used structure-based molecular docking to assess the binding affinities of 60 HF chemicals to the human androgen receptor (AR). Five HF chemicals had relatively high predicted AR binding affinity, suggesting the potential for endocrine disruption. We next assessed androgenic and antiandrogenic activities of these chemicals in vitro. Of the five candidate AR ligands, only Genapol®X-100 significantly modified AR transactivation. To better understand the structural effect of Genapol®X-100 on the potency of AR inhibition, we compared the antiandrogenic activity of Genapol®X-100 with that of its structurally similar chemical, Genapol®X-080. Interestingly, both Genapol®X-100 and Genapol®X-080 elicited an antagonistic effect at AR with 20% relative inhibitory concentrations of 0.43 and 0.89 µM, respectively. Furthermore, we investigated the mechanism of AR inhibition of these two chemicals in vitro, and found that both Genapol®X-100 and Genapol®X-080 inhibited AR through a noncompetitive mechanism. The effect of these two chemicals on the expression of AR responsive genes, e.g. PSA, KLK2, and AR, was also investigated. Genapol®X-100 and Genapol®X-080 altered the expression of these genes. Our findings heighten awareness of endocrine disruption by HF chemicals and provide evidence that noncompetitive antiandrogenic Genapol®X-100 could cause adverse endocrine health effects.


Asunto(s)
Disruptores Endocrinos/toxicidad , Antagonistas de Andrógenos/química , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos , Disruptores Endocrinos/química , Humanos , Fracking Hidráulico , Simulación del Acoplamiento Molecular , Receptores Androgénicos/metabolismo
12.
Prostate ; 80(10): 742-752, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32449811

RESUMEN

BACKGROUND: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells. METHODS: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism. RESULTS: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. CONCLUSIONS: We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.


Asunto(s)
Docetaxel/efectos adversos , Células Asesinas Naturales/efectos de los fármacos , Lectinas Tipo C/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Receptores Androgénicos/inmunología , Receptores de Superficie Celular/inmunología , Antagonistas de Receptores Androgénicos/farmacología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Técnicas de Cocultivo , Terapia Combinada , Curcumina/análogos & derivados , Curcumina/farmacología , Docetaxel/uso terapéutico , Células HEK293 , Humanos , Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/trasplante , Lectinas Tipo C/antagonistas & inhibidores , Lectinas Tipo C/biosíntesis , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/biosíntesis , Regulación hacia Arriba/efectos de los fármacos
13.
J Med Chem ; 63(12): 6513-6522, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32223238

RESUMEN

Orteronel (TAK-700) is a substituted imidazole that was developed for the treatment of castration-resistant prostate cancer but was dropped in phase III clinical trials. Both enantiomers of this inhibitor of cytochrome P450 (P450) 17A1 show some selectivity in differentially blocking the 17α-hydroxylation and lyase activities of the enzyme. Although both enantiomers of this compound have sub-micromolar IC50 values and bind to the enzyme with a type II spectral change (indicative of nitrogen-iron bonding) and reported Kd values of 56 and 40 nM (R and S, respectively), the rates of binding to P450 17A1 were relatively slow. We considered the possibility that the drug is a slow, tight-binding inhibitor. Analysis of the kinetics of binding revealed rapid formation of an initial complex, presumably in the substrate binding site, followed by a slower change to the spectrum of a final iron complex. Similar kinetics were observed in the interaction of another inhibitor, the triazole (S)-seviteronel (VT-464), with P450 17A1. Kinetic tests and modeling indicate that the further change to the iron-complexed form of the orteronel- or seviteronel-P450 complex is not a prerequisite for enzyme inhibition. Accordingly, the inclusion of heme-binding heterocyclic nitrogen moieties in P450 17A1 inhibitors may not be necessary to achieve inhibition but may nevertheless augment the process.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Naftalenos/farmacología , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Triazoles/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Sitios de Unión , Humanos , Hidroxilación , Cinética , Oxidación-Reducción , Conformación Proteica , Esteroide 17-alfa-Hidroxilasa/metabolismo
14.
Eur J Med Chem ; 192: 112156, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32114360

RESUMEN

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 µM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Quinolonas/farmacología , Células 3T3 , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
15.
Eur J Med Chem ; 192: 112196, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32169785

RESUMEN

Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Piridinas/farmacología , Receptores Androgénicos/metabolismo , Tetrahidroisoquinolinas/farmacología , Tiohidantoínas/farmacología , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Tiohidantoínas/síntesis química , Tiohidantoínas/química , Células Tumorales Cultivadas
16.
Cancer Res ; 80(7): 1564-1577, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32029552

RESUMEN

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of prostate cancer. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat prostate cancer and CRPC.Significance: Merging mathematical modeling with experimental data, this study presents the "TRAMP-based platform" as a novel experimental tool to study the in vitro and in vivo evolution of prostate cancer resistance to enzalutamide.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Feniltiohidantoína/farmacología , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Taxoides/farmacología , Taxoides/uso terapéutico
17.
BJU Int ; 125(6): 911-919, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32011085

RESUMEN

OBJECTIVES: To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX). MATERIALS AND METHODS: Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle-treated OVX, low-dose SARM-treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high-dose SARM-treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)-treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak-point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues. RESULTS: (i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (iii) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (v) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats. CONCLUSION: Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth- and striated muscle-mediated urethral function under stress conditions such as sneezing.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Ovariectomía , Vejiga Urinaria/efectos de los fármacos , Incontinencia Urinaria de Esfuerzo , Antagonistas de Receptores Androgénicos/administración & dosificación , Animales , Femenino , Ratas , Ratas Sprague-Dawley , Estornudo/fisiología
18.
Nat Commun ; 11(1): 384, 2020 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-31959826

RESUMEN

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tumores Neuroendocrinos/genética , Neoplasias de la Próstata/genética , Inhibidor de Tripsina Pancreática de Kazal/metabolismo , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Quinasa de la Caseína I/antagonistas & inhibidores , Quinasa de la Caseína I/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Factores de Transcripción SOXB1/metabolismo , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Int J Mol Med ; 45(4): 1195-1202, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31985022

RESUMEN

Echinacoside (ECH) is a natural compound with an endothelium­dependent vasodilatory effect. Nitric oxide (NO) is an important vasorelaxant released from endothelial cells. In order to examine the molecular mechanism of ECH­induced NO production in endothelial cells, the present study investigated the involvement of androgen receptor (AR) and the phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) pathway in the phosphorylation of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVECs). Using the fluorescent probe DAF­FM, the production of NO was found to be significantly increased, and eNOS was phosphorylated at Ser1177 in a concentration­â€‹dependent manner under 0.01­10 µM ECH treatment in HUVECs. In addition, NO production and eNOS phosphorylation induced by ECH were diminished when pretreated with the AR antagonist nilutamide, or when transfected with AR small interfering RNAs. Furthermore, the ECH­induced phosphorylation of the Akt at Ser473 was abrogated by 5 µM wortmannin (a PI3K inhibitor). These data indicated that ECH stimulated NO production via the AR­dependent activation of eNOS in HUVECs, and that the PI3K/Akt pathway may be involved in eNOS phosphorylation induced by ECH.


Asunto(s)
Células Endoteliales/metabolismo , Glicósidos/farmacología , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Línea Celular , Células Endoteliales/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Imidazolidinas/farmacología , Fosforilación/efectos de los fármacos , Receptores Androgénicos/genética , Transducción de Señal/efectos de los fármacos
20.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892584

RESUMEN

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Docetaxel/farmacología , Terapia Molecular Dirigida , Receptores Androgénicos/metabolismo , Taxoides/farmacología , Anciano , Antagonistas de Receptores Androgénicos/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/uso terapéutico , Resultado del Tratamiento
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