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1.
Nat Commun ; 12(1): 1714, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731701

RESUMEN

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-ß induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.


Asunto(s)
Neoplasias Óseas/secundario , Carcinogénesis , Transición Epitelial-Mesenquimal , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Acetilación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencilaminas/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Ciclamas/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Mutación , Osteogénesis , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo
2.
Oncology ; 99(4): 251-255, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33461196

RESUMEN

BACKGROUND: Androgen receptor splice variant V7 (AR-V7) was recently detected in circulating tumor cells of castration-resistant prostate cancer (PC) patients and its expression correlated with resistance to new-generation androgen signaling inhibitors. OBJECTIVES: We retrospectively analyzed whether AR-V7 expression was detectable on radical prostatectomy (RP) specimens of untreated nonmetastatic PC cases, and whether it could be associated with progression after surgery. METHOD: The expression of AR-V7 and AR-FL (full length) was separately evaluated by immunohistochemistry using a streptavidin-biotin-peroxidase system with 2 anti-AR-V7 and anti-AR-FL rabbit monoclonal antibodies. RESULTS: 56 PC cases, classified by their clinical risk, were analyzed. Positive expression was found in 24/32 cases in the high-risk group, 4/13 in the intermediate-risk group, and only 2/11 in the low-risk group. We found a significant correlation between AR-V7 positivity and both risk classification (p < 0.001) and progression after surgery (p < 0.001). CONCLUSIONS: In our population of untreated nonmetastatic PC, AR-V7 is detectable by immunohistochemistry in more than 50% of cases. At this early stage, AR-V7 positivity is associated with risk classification and it can predict progression after surgery.


Asunto(s)
Progresión de la Enfermedad , Prostatectomía/métodos , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/cirugía , Receptores Androgénicos/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Isoformas de Proteínas/metabolismo , Receptores Androgénicos/genética , Estudios Retrospectivos , Riesgo
3.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-33327545

RESUMEN

Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores LHRH/metabolismo , Androstenos/uso terapéutico , Animales , Docetaxel/uso terapéutico , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Masculino , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos
4.
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
5.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32878797

RESUMEN

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Naftoquinonas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/genética , Survivin/genética , Taxoides/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Mensajero/genética , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Anticancer Res ; 40(9): 5107-5114, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32878799

RESUMEN

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) via Sonic Hedgehog (Shh) signaling may be one of the mechanisms of progression of castration-resistant prostate cancer (CRPC). In this study, we investigated the possible therapeutic effect of vismodegib, a new Shh inhibitor, in a mouse CRPC model. MATERIALS AND METHODS: We determined cell proliferation, apoptosis and the expression of EMT-related genes for three prostate cancer cell lines; androgen-dependent LNCaP and independent C4-2B and PC-3 in the presence of vismodegib in vitro. Fifty mg/kg of vismodegib were orally administered into mice bearing C4-2B and PC-3 tumors, respectively every other week for 3 weeks. RESULTS: Vismodegib significantly inhibited cell proliferation and induced cell apoptosis in all cell lines in vitro (p<0.05). Vismodegib significantly inhibited EMT in CRPC cells and tumor growth in C4-2B-bearing mice compared to controls in vivo (p<0.05). Higher expression of caspase-3 and lower expression of vimentin in PC-3 and C4-2B tumors were induced by vismodegib in immunohistochemical analysis. CONCLUSION: Vismodegib inhibited cell proliferation via apoptosis and also suppressed EMT, showing anti-tumor effects in mice. Further mechanistic studies are needed to investigate the feasibility of vismodegib for CRPC treatment.


Asunto(s)
Anilidas/farmacología , Antineoplásicos/farmacología , Proteínas Hedgehog/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Antitumor por Modelo de Xenoinjerto
7.
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
8.
Prostate ; 80(13): 1108-1117, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32628318

RESUMEN

BACKGROUND: Putative castration-resistant (CR) stem-like cells (CRSC) have been identified based on their ability to initiate and drive prostate cancer (PCa) recurrence following castration in vivo. Yet the relevance of these CRSC in the course of the human disease and particularly for the transition from hormone-naive (HN) to castration-resistance is unclear. In this study, we aimed at deciphering the significance of CRSC markers in PCa progression. METHODS: We constructed a tissue microarray comprising 112 matched HN and CR tissue specimens derived from 55 PCa patients. Expression of eight stemness-associated markers (ALDH1A1, ALDH1A3, ALDH3A1, BMI1, NANOG, NKX3.1, OCT4, SOX2) was assessed by immunohistochemistry and scored as a percentage of positive tumor cells. For each marker, the resulting scores were statistically analyzed and compared to pathological and clinical data associated with the samples. Unsupervised clustering analysis was performed to stratify patients according to the expression of the eight CRSC markers. Publicly-available transcriptional datasets comprising HN and CR PCa samples were interrogated to assess the expression of the factors in silico. RESULTS: Immunohistochemical assessment of paired samples revealed atypical patterns of expression and intra- and intertumor heterogeneity for a subset of CRSC markers. While the expression of particular CRSC markers was dynamic over time in some patients, none of the markers showed significant changes in expression upon the development of castration resistance (CR vs HN). Using unsupervised clustering approaches, we identified phenotypic subtypes based on the expression of specific stem-associated markers. In particular, we found (a) patterns of mutual exclusivity for ALDH1A1 and ALDH1A3 expression, which was also observed at the transcriptomic level in publicly-available PCa datasets, and (b) a phenotypic cluster associated with more aggressive features. Finally, by comparing HN and CR matched samples, we identified phenotypic cluster switches (ie, change of phenotypic cluster between the HN and CR state), that may be associated with clinical and predictive relevance. CONCLUSIONS: Our findings indicate stemness-associated patterns that are associated with the development of castration-resistance. These results pave the way toward a deeper understanding of the relevance of CRSC markers in PCa progression and resistance to androgen-deprivation therapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , /genética , Aldehído Oxidorreductasas/genética , Aldehído Oxidorreductasas/metabolismo , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Heterogeneidad Genética , Humanos , Inmunohistoquímica , Masculino , Neoplasias de la Próstata Resistentes a la Castración/genética , Retinal-Deshidrogenasa/genética , Retinal-Deshidrogenasa/metabolismo , Análisis de Matrices Tisulares
9.
Clin Nucl Med ; 45(10): 805-807, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32604118

RESUMEN

A 56-year-old man with metastatic castration-resistant prostate cancer was referred for radioligand therapy with Lu-prostate-specific membrane antigen. In the third cycle, a posttherapy whole-body scan showed unexpected skeletal and joint uptake apart from his known metastatic lesions. This observation raised suspicion for possible impurity (mainly free lutetium) in the applied radiopharmaceutical product. After contacting the radiopharmaceutical company, we were informed that the radiochemical purity of the used batch of Lu-prostate-specific membrane antigen had been 95%. This is the first report of excess free lutetium scan pattern and its complications in a patient undergoing radioligand therapy.


Asunto(s)
Cloruros/metabolismo , Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/patología , Imagen de Cuerpo Entero , Artefactos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Resultado del Tratamiento
10.
Prostate ; 80(13): 1087-1096, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32609927

RESUMEN

BACKGROUND: Prostate cancer is the second most common cancer worldwide. Tumor microenvironment is composed of activated fibroblasts, the so called carcinoma-associated fibroblasts (CAFs). They express high levels of α-smooth muscle actin (α-SMA) and type I collagen (COL1), and support proliferation and migration of tumor epithelial cells. Extracorporeal shock waves (ESWs), acoustic waves, are effective in the treatment of hypertrophic scars, due to their ability to modulate fibrosis. Based on this rationale, the study evaluated the effects of ESWs on CAF activation and the influence of ESW-treated CAFs on the growth and migration of epithelial prostatic carcinoma cells. METHODS: Primary cultures of CAFs (n = 10) were prepared from tumors of patients undergoing surgery for high-risk prostate carcinoma. CAFs were treated with ESWs (energy levels: 0.32 mJ/mm2 , 1000 pulses; 0.59 mJ/mm2 , 250 pulses). After treatment, the messenger RNA and protein levels of the stromal activation markers α-SMA and COL1 were determined. Subsequently, two different stabilized cell lines (PC3 and DU145) of androgen-resistant prostate cancer were treated with the conditioned media produced by ESW-treated CAFs. At different times, viability and migration of PC3 and DU145 cells were evaluated. Viability was also assessed by coculture system using CAFs and PC3 or DU145 cells. RESULTS: ESWs reduced gene expression and protein level of α-SMA and COL1 in CAFs. The treatment of PC3 and DU145 with conditioned media of ESW-treated CAFs determined a reduction of their growth and invasive potential. Coculture systems between ESW-treated CAFs and PC3 or DU145 cells confirmed the epithelial cell number reduction. CONCLUSIONS: This in vitro study demonstrates for the first time that ESWs are able to modulate the activation of prostate CAFs in favor of a less "reactive" stroma, with consequent slowing of the growth and migration of prostate cancer epithelial cells. However, only further studies to be performed in vivo will confirm the possibility of using this new therapy in patients with prostate cancer.


Asunto(s)
Tratamiento con Ondas de Choque Extracorpóreas/métodos , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Células del Estroma/patología , Actinas/genética , Actinas/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Progresión de la Enfermedad , Humanos , Masculino , Células PC-3 , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células del Estroma/metabolismo
11.
Prostate ; 80(13): 1058-1070, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32692871

RESUMEN

BACKGROUND: Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cells in vitro. However, the status of NFIB in prostate cancer was unknown. METHODS: We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlate NFIB expression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blot analysis and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed co-immunoprecipitation studies to determine if NFIB and AR interact. RESULTS: NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castration-resistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples, NFIB expression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through co-immunoprecipitation experiments. CONCLUSION: We have described the expression pattern of NFIB in primary and castration-resistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.


Asunto(s)
Factores de Transcripción NFI/biosíntesis , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Línea Celular Tumoral , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Factores de Transcripción NFI/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Análisis de Matrices Tisulares , Transcriptoma
12.
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
13.
Expert Opin Pharmacother ; 21(13): 1537-1546, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32543237

RESUMEN

INTRODUCTION: Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer. AREAS COVERED: The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database. EXPERT OPINION: Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Nat Commun ; 11(1): 2689, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32483206

RESUMEN

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.


Asunto(s)
Clorgilina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Fenelzina/farmacología , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Empalme Alternativo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Estabilidad de Enzimas , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Monoaminooxidasa/química , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Células Neoplásicas Circulantes/metabolismo , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Expert Opin Pharmacother ; 21(12): 1431-1448, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32469248

RESUMEN

INTRODUCTION: Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC. AREAS COVERED: In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression. EXPERT OPINION: Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Inmunoterapia/métodos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/uso terapéutico , Androstenos/administración & dosificación , Androstenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Humanos , Masculino , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Radio (Elemento)/administración & dosificación , Radio (Elemento)/uso terapéutico , Taxoides/administración & dosificación , Taxoides/uso terapéutico , Extractos de Tejidos/administración & dosificación , Extractos de Tejidos/uso terapéutico
16.
Orv Hetil ; 161(20): 813-820, 2020 05 01.
Artículo en Húngaro | MEDLINE | ID: mdl-32364360

RESUMEN

In the last few years, several new drugs with various mechanisms of action have been approved for the treatment of castration-resistant prostate cancer. Due to this development, therapeutic decision-making has become increasingly complex. Therefore, therapy selection as well as timing and sequence of treatments need to be optimized in an individual manner. In addition, also for these novel therapies, baseline and acquired as well as cross-resistance have been observed. Underlying mechanisms become increasingly clear, resulting in a shift from empiric-based towards rational-based therapeutic decision-making. In the present review, we provide an overview on the resistance mechanisms against the most frequently applied systemic treatments of metastatic castration-resistant prostate cancer such as docetaxel, abiraterone and enzalutamide. We summarize - among others - the mechanisms by MDR (multidrug-resistant) protein expression, alterations of androgen receptor, Wnt, p53 and DNA-repair pathways (BRCA/ATM) as well as resistance through therapy-induced neuroendocrine differentiation of the tumour. Orv Hetil. 2020; 161(20): 813-820.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Androstenos/uso terapéutico , Docetaxel/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Masculino , Metástasis de la Neoplasia , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Resultado del Tratamiento
17.
Int J Nanomedicine ; 15: 3087-3098, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32431503

RESUMEN

Purpose: Aldo-ketoreductase (AKR) 1C3 is crucial for testosterone synthesis. Abnormally high expression/activity of AKR1C3 can promote castration-resistant prostate cancer (CRPC). A mansonone derivative and AKR1C3 inhibitor, 6e, was combined with 4D5 (extracellular fragment of the monoclonal antibody of human epidermal growth factor receptor-2)-modified chitosan to achieve a nanodrug-delivery system (CS-4D5/6e) to treat CRPC. Materials and Methods: Morphologies/properties of CS-4D5/6e were characterized by atomic force microscopy, zeta-potential analysis, and Fourier transform-infrared spectroscopy. CS-4D5/6e uptake was measured by immunofluorescence under confocal laser scanning microscopy. Testosterone in LNCaP cells overexpressing human AKR1C3 (LNCaP-AKR1C3) and cell lysates was measured to reflect AKR1C3 activity. Androgen receptor (AR) and prostate-specific antigen (PSA) expression was measured by Western blotting. CS-4D5/6e-based inhibition of AKR1C3 was evaluated in tumor-xenografted mice. Results: CS-4D5/6e was oblate, with a particle size of 200-300 nm and thickness of 1-5 nm. Zeta potential was 1.39±0.248 mV. 6e content in CS-4D5/6e was 7.3±1.4% and was 18±3.6% for 4D5. 6e and CS-4D5/6e inhibited testosterone production significantly in a concentration-dependent manner in LNCaP-AKR1C3 cells, and a decrease in expression of AKR1C3, PSA, and AR was noted. Half-maximal inhibitory concentration of CS-4D5/6e on LNCaP-AKR1C3 cells was significantly lower than that in LNCaP cells (P<0.05). CS-4D5/6e significantly reduced growth of 22Rv1 tumor xenografts by 57.00% compared with that in the vehicle group (P<0.01). Conclusion: We demonstrated the antineoplastic activity of a potent AKR1C3 inhibitor (6e) and its nanodrug-delivery system (CS-4D5/6e). First, CS-4D5/6e targeted HER2-positive CRPC cells. Second, it transferred 6e (an AKR1C3 inhibitor) to achieve a reduction in intratumoral testosterone production. Compared with 6e, CS-4D5/6e showed lower systemic toxicity. CS-4D5/6e inhibited tumor growth effectively in mice implanted with tumor xenografts by downregulating testosterone production mediated by intratumoral AKR1C3. These results showed a promising strategy for treatment of the CRPC that develops invariably in prostate-cancer patients.


Asunto(s)
Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/química , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Quitosano/química , Sistemas de Liberación de Medicamentos/métodos , Humanos , Masculino , Ratones Endogámicos BALB C , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Naftoquinonas/química , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptor ErbB-2/inmunología , Receptores Androgénicos/metabolismo , Sesquiterpenos/química , Testosterona/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Prostate ; 80(11): 799-810, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32449815

RESUMEN

BACKGROUND: Regulator of G-protein signaling 2 (RGS2) is a multifaceted protein with a prognostic value in hormone-naïve prostate cancer (PC). It has previously been associated with the development of castration resistance. However, RGS2 expression in clinical specimens of castration-resistant prostate cancer (CRPC) and its clinical relevance has not been explored. In the present study, RGS2 was assessed in CRPC and in relation to the development of castration resistance. METHODS: In the present study, RGS2 expression was evaluated with immunohistochemistry in patient materials of hormone-naïve and castration-resistant primary tumors, also in matched specimens before and after 3 months of androgen deprivation therapy (ADT). Cox regression and Kaplan-Meier curves were used to evaluate the clinical significance of RGS2 expression. RGS2 expression in association to castration-resistant growth was assessed experimentally in an orthotopic xenograft mouse model of CRPC. In vitro, hormone depletion of LNCaP and enzalutamide treatment of LNCaP, 22Rv1, and VCaP was performed to evaluate the association between RGS2 and the androgen receptor (AR). Stable RGS2 knockdown was used to evaluate the impact of RGS2 in association to PC cell growth under hormone-reduced conditions. Gene and protein expression were evaluated with quantitative polymerase chain reaction and Western blot analysis, respectively. RESULTS: RGS2 expression is increased in CRPC and enriched under ADT. Furthermore, a high RGS2 level is prognostic for poor cancer-specific survival for CRPC patients and significantly reduced failure-free survival (FFS) after an initiated ADT. Additionally, the prognostic value of RGS2 outperforms prostate-specific antigen (PSA) in terms of FFS. The present study furthermore suggests that RGS2 expression is reflective of AR activity. Moreover, low RGS2-expressing cells display hampered growth under hormone-reduced conditions, in line with the poor prognosis associated with high RGS2 expression. CONCLUSIONS: High levels of RGS2 are associated with aggressive forms of castration-resistant PC. The results demonstrate that a high level of RGS2 is associated with poor prognosis in association with castration-resistant PC growth. RGS2 alone, or in association with PSA, has the potential to identify patients that require additional treatment at an early stage during ADT.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proteínas RGS/biosíntesis , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Animales , Línea Celular Tumoral , Estudios de Cohortes , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Tasa de Supervivencia , Regulación hacia Arriba
19.
Proc Natl Acad Sci U S A ; 117(22): 12315-12323, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32424106

RESUMEN

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.


Asunto(s)
Antineoplásicos/administración & dosificación , Resistencia a Antineoplásicos , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/administración & dosificación , Receptores Androgénicos/genética , Anciano , Anciano de 80 o más Años , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Feniltiohidantoína/administración & dosificación , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/metabolismo
20.
Rev Med Suisse ; 16(695): 1098-1101, 2020 May 27.
Artículo en Francés | MEDLINE | ID: mdl-32462838

RESUMEN

For decades, androgen deprivation was the standard of care for metastatic prostate cancer. Chemotherapy, then novel anti-androgen therapies, changed the treatment paradigm. Large phase III randomized clinical trials were conducted over the course of the last decade, first among patients with castration resistant prostate cancer, then among those with hormone-sensitive disease. Today, androgen deprivation therapy alone is no longer the gold standard and should be associated either with chemotherapy in high-volume disease, or novel anti-androgen therapy. As such, each case should be discussed with a specialist to choose the most appropriate treatment.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Andrógenos/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia
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