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1.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878797

RESUMO

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.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Survivina/genética , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 40(9): 5107-5114, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878799

RESUMO

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.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Proteínas Hedgehog/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Life Sci ; 259: 118208, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763294

RESUMO

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.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/metabolismo , Androgênios/metabolismo , Terapia Combinada/métodos , Progressão da Doença , Quimioterapia Combinada/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Estudos Prospectivos , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
Prostate ; 80(13): 1058-1070, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32692871

RESUMO

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.


Assuntos
Fatores de Transcrição NFI/biossíntese , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Fatores de Transcrição NFI/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Análise Serial de Tecidos , Transcriptoma
5.
Prostate ; 80(13): 1108-1117, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32628318

RESUMO

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.


Assuntos
Biomarcadores Tumorais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , /genética , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Biomarcadores Tumorais/genética , Progressão da Doença , Heterogeneidade Genética , Humanos , Imuno-Histoquímica , Masculino , Neoplasias de Próstata Resistentes à Castração/genética , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Análise Serial de Tecidos
6.
Clin Nucl Med ; 45(10): 805-807, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32604118

RESUMO

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.


Assuntos
Cloretos/metabolismo , Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Imagem Corporal Total , Artefatos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/metabolismo , Resultado do Tratamento
7.
Prostate ; 80(13): 1087-1096, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32609927

RESUMO

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.


Assuntos
Tratamento por Ondas de Choque Extracorpóreas/métodos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Células Estromais/patologia , Actinas/genética , Actinas/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Progressão da Doença , Humanos , Masculino , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Estromais/metabolismo
8.
Nat Commun ; 11(1): 2689, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483206

RESUMO

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.


Assuntos
Clorgilina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fenelzina/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estabilidade Enzimática , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Células Neoplásicas Circulantes/metabolismo , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Prostate ; 80(11): 885-894, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483877

RESUMO

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.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo
10.
Expert Opin Pharmacother ; 21(13): 1537-1546, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32543237

RESUMO

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.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Proc Natl Acad Sci U S A ; 117(22): 12315-12323, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424106

RESUMO

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.


Assuntos
Antineoplásicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/administração & dosagem , Receptores Androgênicos/genética , Idoso , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/administração & dosagem , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo
12.
Orv Hetil ; 161(20): 813-820, 2020 05 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32364360

RESUMO

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.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androstenos/uso terapêutico , Docetaxel/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Metástase Neoplásica , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Resultado do Tratamento
13.
Expert Opin Pharmacother ; 21(12): 1431-1448, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32469248

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/uso terapêutico , Androstenos/administração & dosagem , Androstenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Humanos , Masculino , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Rádio (Elemento)/administração & dosagem , Rádio (Elemento)/uso terapêutico , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Extratos de Tecidos/administração & dosagem , Extratos de Tecidos/uso terapêutico
14.
Rev Med Suisse ; 16(695): 1098-1101, 2020 May 27.
Artigo em Francês | MEDLINE | ID: mdl-32462838

RESUMO

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.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Androgênios/metabolismo , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia
15.
Int J Nanomedicine ; 15: 3087-3098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431503

RESUMO

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.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Terapia de Alvo Molecular/métodos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Naftoquinonas/química , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptor ErbB-2/imunologia , Receptores Androgênicos/metabolismo , Sesquiterpenos/química , Testosterona/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Prostate ; 80(11): 799-810, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449815

RESUMO

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.


Assuntos
Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteínas RGS/biossíntese , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Animais , Linhagem Celular Tumoral , Estudos de Coortes , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Taxa de Sobrevida , Regulação para Cima
17.
Prostate ; 80(9): 674-686, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32294305

RESUMO

BACKGROUND: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. MicroRNA-30a (miR-30a) has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet. METHODS: The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a. The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets. RESULTS: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells. CONCLUSIONS: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , MicroRNAs/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição SOXC/metabolismo , Transativadores/metabolismo , Antagonistas de Androgênios/metabolismo , Androgênios/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo , Fatores de Transcrição Forkhead/genética , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOXC/genética , Transativadores/genética , Regulação para Cima
18.
Cancer Res ; 80(13): 2927-2939, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32341037

RESUMO

In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Retroalimentação Fisiológica , Fatores Reguladores de Interferon/metabolismo , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Feniltioidantoína/farmacologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Oxid Med Cell Longev ; 2020: 6724810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215176

RESUMO

Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Quinase C Ativada/metabolismo , Canais de Cátion TRPM/genética , Anexina A1/genética , Anexina A1/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Fosforilação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Hipóxia Tumoral
20.
Oncogene ; 39(20): 4014-4027, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205868

RESUMO

Prostate cancer (PCa) innervation contributes to the progression of PCa. However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa clinical specimens compared with all other cancer types, and that amplification or gain of their corresponding encoding genes (CHRM1 and CHRM3, respectively) represent a worse prognostic factor for PCa progression free survival. Moreover, m1 and m3 gene gain or amplification is frequent in castration-resistant PCa (CRPC) compared with hormone-sensitive PCa (HSPC) specimens. This was reflected in HSPC-derived cells, which show aberrantly high expression of m1 and m3 under androgen deprivation mimicking castration and androgen receptor inhibition. We also show that pharmacological activation of m1 and m3 signaling is sufficient to induce the castration-resistant growth of PCa cells. Mechanistically, we found that m1 and m3 stimulation induces YAP activation through FAK, whose encoding gene, PTK2 is frequently amplified in CRPC cases. Pharmacological inhibition of FAK and knockdown of YAP abolished m1 and m3-induced castration-resistant growth of PCa cells. Our findings provide novel therapeutic opportunities for muscarinic-signal-driven CRPC progression by targeting the FAK-YAP signaling axis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptor Muscarínico M1/biossíntese , Receptor Muscarínico M3/biossíntese , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quinase 1 de Adesão Focal/genética , Humanos , Masculino , Proteínas de Neoplasias/genética , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptor Muscarínico M1/genética , Receptor Muscarínico M3/genética , Fatores de Transcrição/genética
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