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1.
Anticancer Res ; 41(4): 2101-2110, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813420

RESUMEN

BACKGROUND/AIM: To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients. PATIENTS AND METHODS: Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids. RESULTS: Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance. CONCLUSION: Topical medications might have a role in radiation proctitis prevention.


Asunto(s)
Antiinflamatorios/administración & dosificación , Proctitis/prevención & control , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Radioterapia de Intensidad Modulada , Administración Tópica , Anciano , Anciano de 80 o más Años , Beclometasona/administración & dosificación , Enema/métodos , Humanos , Ácido Hialurónico/administración & dosificación , Italia , Masculino , Persona de Mediana Edad , Tratamientos Conservadores del Órgano/métodos , Proctitis/etiología , Neoplasias de la Próstata/patología , Hipofraccionamiento de la Dosis de Radiación , Traumatismos por Radiación/prevención & control , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos
2.
Compend Contin Educ Dent ; 42(2): 62-67; quiz 68, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33735578

RESUMEN

Prostate cancer is the most frequently diagnosed cancer among elderly men in the United States. Skeletal architecture is affected by metastasis and androgen deprivation therapy (ADT), which is considered a gold standard treatment in prostate cancer. Osteoporosis and skeletal effects are reported among most patients on ADT. To counter these effects and to reduce bone turnover, antiresorptive drugs such as bisphosphonates and denosumab are commonly prescribed in prostate cancer. These drugs increase the prevalence of osteonecrosis of the jaw in a subset of patients. The future should hold promise for new drugs that could have a positive impact on bone metabolism without jeopardizing bone integrity.


Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Neoplasias de la Próstata , Anciano , Antagonistas de Andrógenos/efectos adversos , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Conservadores de la Densidad Ósea/efectos adversos , Denosumab/efectos adversos , Difosfonatos , Humanos , Maxilares , Masculino , Neoplasias de la Próstata/tratamiento farmacológico
3.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673346

RESUMEN

2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer.


Asunto(s)
2-Metoxiestradiol/farmacología , Reposicionamiento de Medicamentos , Proteínas de Neoplasias , Neoplasias de la Próstata , Proteínas Tirosina Quinasas Receptoras , Animales , Humanos , Masculino , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Células PC-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo
5.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672769

RESUMEN

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


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Proteolisis/efectos de los fármacos
6.
Anticancer Res ; 41(3): 1197-1202, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788710

RESUMEN

BACKGROUND/AIM: Previous studies have shown that the sandalwood oil constituent α-santalol inhibits growth of cultured human prostate cancer cells in vitro and PC-3 prostate cancer xenografts. Along with the studies from our laboratory, it is well established that α-santalol targets the phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT serine/ threonine kinase 1 (AKT) pathway to induce apoptosis but its growth-suppressive effects have not been fully elucidated. The current study was undertaken to investigate the role of autophagy in α-santalol-induced prostate cancer cell death. MATERIALS AND METHODS: Cell lines LNCaP and PC-3 were maintained in an atmosphere of 95% air and 5% CO2 at 37°C. Trypan blue dye exclusion assay was employed to assess the effects of α-santalol with/without 3-methyl adenine on the cell viability of prostate cancer cells. Acidic vesicular organelles induced by α-santalol treatment were detected by staining with acridine orange. Immunofluorescence and immunoblotting were performed to analyze expression of proteins involved in the AKT-mammalian target of rapamycin (mTOR) pathway. RESULTS: LNCaP and PC-3 cells upon treatment with α-santalol resulted in characteristic features analogous to autophagic response, including formation of acidic vesicular organelles, recruitment and cleavage of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. Alpha-santalol treatment further suppressed phosphorylation of activated AKT and mTOR, which are critical regulators of autophagic response. In addition, pre-treatment of PC-3 cells with specific inhibitor of autophagy (3-methyladenine) and co-treatment with α-santalol attenuated the expression of LC3-II and phospho-AKT, and significantly reduced the cell viability. CONCLUSION: The present study indicates that α-santalol induces autophagy by targeting the AKT-mTOR pathway in prostate cancer cells, which may serve as a protective mechanism.


Asunto(s)
Autofagia/efectos de los fármacos , Sesquiterpenos Policíclicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/farmacología , Apoptosis/efectos de los fármacos , Autofagia/fisiología , Línea Celular Tumoral , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo
7.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753739

RESUMEN

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Asunto(s)
Carcinogénesis/metabolismo , Hexoquinasa/metabolismo , Mitocondrias/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Docetaxel/farmacología , Hexoquinasa/genética , Humanos , Masculino , Ratones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Unión Proteica , Sumoilación , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
8.
Hinyokika Kiyo ; 67(1): 43-46, 2021 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-33535297

RESUMEN

A 67-year-old male came to our department with complaints of urinary retention and gross hematuria. The prostate specific antigen (PSA) level in the serum was elevated to 69.5 ng/ml. Thus a transperineal prostate biopsy was performed. The patient was diagnosed with prostate cancer, and lung and bone metastases were also revealed. Treatment for metastatic prostate cancer was performed for approximately 5 years with combined androgen blockade therapy followed by enzalutamide, docetaxel, estramustine, Ra-223 dichloride, estradiol, and then enzalutamide reintroduction. Thereafter, the patient presented with bilateral breast nodules and we referred him to our breast surgery department. Breast needle biopsy findings revealed breast metastasis from prostate cancer, that was not primary breast cancer. The patient underwent a bilateral mastectomy.


Asunto(s)
Adenocarcinoma , Neoplasias de la Mama , Neoplasias de la Próstata , Radio (Elemento) , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Anciano , Humanos , Masculino , Mastectomía , Antígeno Prostático Específico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía
9.
Hinyokika Kiyo ; 67(1): 47-51, 2021 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-33535298

RESUMEN

A 53-year-old man was diagnosed with prostate cancer with multiple bone metastasis. Therefore androgen deprivation therapy was initiated. After treatment with denosumab injection for bone metastasis, hypocalcemia and hypophosphatemia occurred. Despite treatment for hypocalcemia with vitamin D and calcium lactate,his serum calcium and phosphate levels were refractory to treatment. The etiology of hypophosphatemia was investigated,and the level of serum fibroblast growth factor 23 (FGF23) was abnormally elevated. Three months after the first measurement of FGF23,the patient died of prostate cancer. Severe hypophosphatemia is a typical manifestation of tumor-induced hypophosphatemic osteomalacia (TIO),which is a paraneoplastic condition, mediated by FGF23 overexpression in most cases. His osteoblastic metastasis,however,did not meet the disease criteria of osteomalacia. Several reports have suggested that excessive FGF23 may mediate both severe hypophosphatemia and aggressive castrationresistant prostate cancer characteristics. Management of serum FGF23 may be a novel therapeutic strategy for castration-resistant prostate cancer with hypophosphatemia.


Asunto(s)
Hipocalcemia , Hipofosfatemia , Neoplasias de la Próstata , Antagonistas de Andrógenos , Factores de Crecimiento de Fibroblastos , Humanos , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/etiología , Hipofosfatemia/etiología , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/tratamiento farmacológico
10.
AAPS PharmSciTech ; 22(2): 73, 2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33586081

RESUMEN

Degarelix is a gonadotropin-releasing hormone (GnRH) receptor antagonist. Upon contact with physiological fluid, degarelix undergoes quick gelation and forms a depot at the site of injection providing sustained release. The molecular gelling kinetics is a critical physiochemical quality attribute of degarelix products that may impact drug delivery. However, high-resolution and drug substance (DS)-specific analytical methods for characterizing gelling kinetics of degarelix are still lacking. Accordingly, the current study focused on developing NMR-based methods to characterize in vitro initial aggregation of degarelix in Firmagon® drug product (DP). The high-precision real-time NMR method was demonstrated to quickly differentiate lot to lot differences in degarelix aggregation kinetics, and to reveal the effects of degarelix concentration, pH, salt, and temperature on the kinetics. The results could be useful for quality assurance of degarelix products and facilitate complex generic drug development. The real-time NMR method developed here could also be adopted to other complex DPs that have varied aggregation and release properties.


Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Oligopéptidos/química , Desarrollo de Medicamentos , Humanos , Cinética , Masculino , Neoplasias de la Próstata/tratamiento farmacológico
11.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33567533

RESUMEN

Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.


Asunto(s)
Neoplasias de la Mama/patología , Movimiento Celular , Descubrimiento de Drogas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Próstata/patología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
JAMA Netw Open ; 4(2): e210070, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33625512

RESUMEN

Importance: Cardiovascular disease is a leading cause of mortality in patients with prostate cancer, and androgen deprivation therapy (ADT) may worsen cardiovascular risk. Adherence to guideline-recommended assessment and management of cardiovascular risk factors (CVRFs) in patients initiating ADT is unknown. Objective: To describe CVRF assessment and management in men with prostate cancer initiating ADT and overall. Design, Setting, and Participants: A cross-sectional analysis of 90 494 men treated within the US Veterans Health Administration diagnosed with prostate cancer between January 1, 2010, and December 31, 2017, was conducted. Participants included men with a history of atherosclerotic cardiovascular disease (ASCVD), and treatment with ADT within 1 year of diagnosis. Data analysis was conducted from September 10, 2019, to July 1, 2020. Main Outcomes and Measures: Rates of comprehensive CVRF assessment, uncontrolled CVRFs, and untreated CVRFs. Comprehensive CVRF assessment was defined as recorded measures for blood pressure, cholesterol, and glucose levels; CVRF control as blood pressure lower than 140/90 mm Hg, low-density lipoprotein cholesterol 130 mg/dL, and hemoglobin A1c less than 7%; and CVRF treatment as receipt of cardiac risk-reducing medications. Multivariable risk difference regression assessed the association between ASCVD and initiation of ADT and these outcomes. Results: Of 90 494 veterans, median age was 66 years (interquartile range, 62-70 years); and 22 700 men (25.1%) received ADT. Overall, 68.1% (95% CI, 67.8%-68.3%) of the men received comprehensive CVRF assessment; 54.1% (95% CI. 53.7%-54.4%) of those assessed had uncontrolled CVRFs, and 29.6% (95% CI, 29.2%-30.0%) of those with uncontrolled CVRFs were not receiving corresponding cardiac risk-reducing medication. Compared with the reference group of patients without ASCVD not receiving ADT, patients with ASCVD not receiving ADT had a 10.4% (95% CI, 9.5%-11.3%) higher probability of comprehensive CVRF assessment, 4.0% (95% CI, 2.9%-5.1%) lower risk of uncontrolled CVRFs, and 22.2% (95% CI, 21.1%-23.3%) lower risk of untreated CVRFs. Similar differences were observed in patients with ASCVD receiving ADT. In contrast, patients without ASCVD receiving ADT had only a 3.0% (95% CI, 2.1%-3.9%) higher probability of comprehensive CVRF assessment, 2.6% (95% CI, 1.6%-3.5%) higher risk of uncontrolled CVRFs, and 5.4% (95% CI, 4.2%-6.6%) lower risk of untreated CVRFs. Conclusions and Relevance: These findings suggest that veterans with prostate cancer had a high rate of underassessed and undertreated CVRFs, and ADT initiation was not associated with substantial improvements in CVRF assessment or management. These findings highlight gaps in care and the need for interventions to improve CVRF mitigation in this population.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Antihipertensivos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Hipercolesterolemia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Glucemia/metabolismo , Estudios Transversales , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Hemoglobina A Glucada/metabolismo , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/epidemiología , Hipercolesterolemia/metabolismo , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/epidemiología , Medición de Riesgo , Estados Unidos , Veteranos
13.
Nat Commun ; 12(1): 723, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33526787

RESUMEN

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Óseas/secundario , Células Madre Mesenquimatosas/patología , Neoplasias de la Próstata/patología , Receptores de Interferón/metabolismo , Ácidos Aminosalicílicos/farmacología , Ácidos Aminosalicílicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Docetaxel/farmacología , Docetaxel/uso terapéutico , Humanos , Interferones/genética , Interferones/metabolismo , Masculino , Ratones Noqueados , Osteoblastos/patología , Cultivo Primario de Células , Neoplasias de la Próstata/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Receptores de Interferón/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Tibia/patología
14.
Brain Nerve ; 73(2): 179-182, 2021 Feb.
Artículo en Japonés | MEDLINE | ID: mdl-33561832

RESUMEN

An 80-year-old man was diagnosed with prostate cancer in April 2014 and underwent anticancer treatment. His serum prostate-specific antigen (PSA) level was abruptly increased on December 26, 2014. He was admitted to the neurological department of our hospital on January 14, 2015, because of the appearance of staggering gait and diplopia. Neurological examination revealed marked opsoclonus, limb ataxia and ataxic gait. The patient was diagnosed with paraneoplastic opsoclonus and ataxia caused by prostate cancer relapse. Steroid pulse therapy was initiated and his symptoms, including opsoclonus and ataxia, markedly improved. Although most cases of paraneoplastic opsoclonus precede the discovery of cancer, our case developed symptoms simultaneously with relapse and acute progression of prostate cancer. Paraneoplastic opsoclonus with prostate cancer is rare. Additionally, our case showed excellent response of opsoclonus to steroid therapy without treatment of the underlying disease. (Received June 1, 2020; Accepted September 18, 2020; Published February 1, 2021).


Asunto(s)
Ataxia Cerebelosa , Trastornos de la Motilidad Ocular , Neoplasias de la Próstata , Anciano de 80 o más Años , Ataxia/tratamiento farmacológico , Ataxia/etiología , Humanos , Masculino , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/tratamiento farmacológico
15.
Cell Transplant ; 30: 963689721991477, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33522308

RESUMEN

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


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/complicaciones , Antagonistas de Estrógenos/uso terapéutico , Neoplasias de la Próstata/complicaciones , Tamoxifeno/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , /metabolismo , Descubrimiento de Drogas , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/análisis , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/análisis , Serina Endopeptidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacología
16.
ACS Appl Mater Interfaces ; 13(7): 7945-7954, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33588525

RESUMEN

HJS and DHJS, two near-infrared emissive and mitochondria-targeted therapy probes, have been designed. They exhibited photothermal & photodynamic cytotoxicity and aggregation-induced emission (AIE) characteristics. Interestingly, we could receive fluorescence immediately after adding the probes without washing in 1 min. They could quickly enter cancer cells and selectively localized to the mitochondria firstly. When the concentration of probes was low (<5 µM), they could respond sensitively to the mitochondrial membrane potential and would selectively enter the mitochondria with red fluorescence. However, when the concentration was high (≥5 µM), they would preferentially enter the mitochondria and have the property of dual-channel fluorescence imaging (red and near-infrared) even after 24 h. What's more, they increased the intracellular reactive oxygen species (ROS) levels, decreased the mitochondrial membrane potentials, and then induced apoptosis, which were proved by confocal imaging and flow cytometry experiments. In addition, the results of photothermal experiment and cytotoxicity test showed that the probes had good photothermal and photodynamic toxicity to cancer cells. In vitro and in vivo experiments also proved the excellent near-infrared (NIR) imaging ability, good biocompatibility and certain inhibition of tumor growth ability of DHJS.


Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Mitocondrias/efectos de los fármacos , Fotoquimioterapia , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/química , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Imagen Óptica , Células PC-3 , Tamaño de la Partícula , Neoplasias de la Próstata/diagnóstico por imagen , Propiedades de Superficie , Células Tumorales Cultivadas
17.
Mutat Res ; 861-862: 503306, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33551100

RESUMEN

Inhibiting inflammatory processes or eliminating inflammation represents a logical role in the suppression and treatment strategy of cancer. Several studies have shown that anti-inflammatory drugs (NSAIDs) act as anticancer agents while reducing metastases and mortality rate. NSAIDs are seriously limited by their side effects and toxicity, which can become cumulative with their long-term administration for chemoprevention. In the current ex vivo / in vitro study, the genotoxicity mechanisms of NSAIDS in bulk and nanoparticle forms allowed a strategy to prevent and minimise the damage in human lymphocytes. When compared to their bulk forms, acetylsalicylic acid (Aspirin) nano and ibuprofen nano (IBU N), both NSAIDs in 500 µg/mL concentration significantly decreased DNA damage measured by alkaline comet assay. Micronuclei (MNi) frequency also decreased after ASP N (500 µg/mL), ASP B (500 µg/mL) and IBU N (200 µg/mL) in prostate cancer patients and healthy individuals, however, the ibuprofen bulk (200 µg/mL) showed a significant increase in MNi formation in lymphocytes from healthy and prostate cancer patients when compared to the respective untreated lymphocytes. These findings suggest that a reduction in particle size had an impact on the reactivity of the drug, further emphasising the potential of nanoparticles to improve the current treatment options.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Aberraciones Cromosómicas/efectos de los fármacos , Daño del ADN , Ibuprofeno/farmacología , Linfocitos/patología , Neoplasias de la Próstata/patología , Anciano , Estudios de Casos y Controles , Humanos , Técnicas In Vitro , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Nanopartículas , Neoplasias de la Próstata/tratamiento farmacológico
18.
Adv Exp Med Biol ; 1290: 1-8, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33559852

RESUMEN

Interleukin-6 (IL-6) is a proinflammatory cytokine, which is involved in pathogenesis of several cancers. Its expression and function in prostate cancer have been extensively studied in cellular models and clinical specimens. High levels of IL-6 were detected in conditioned media from cells which do not respond to androgens. Increased phosphorylation of signal transducer and activator of transcription (STAT)3 factor which is induced in response to IL-6 is one of the typical features of prostate cancer. However, reports in the literature show regulation of neuroendocrine phenotype by IL-6. Effects of IL-6 on stimulation of proliferation, migration, and invasion lead to the establishment of experimental and clinical approaches to target IL-6. In prostate cancer, anti-IL-6 antibodies were demonstrated to inhibit growth in vitro and in vivo. Clinically, application of anti-IL-6 therapies did not improve survival of patients with metastatic prostate cancer. However, clinical trial design in the future may include different treatment schedule and combinations with experimental and clinical therapies. Endogenous inhibitors of IL-6 such as suppressors of cytokine signaling and protein inhibitors of activated STAT have variable effects on prostate cells, depending on presence or absence of the androgen receptor.


Asunto(s)
Interleucina-6 , Neoplasias de la Próstata , Humanos , Interleucina-6/metabolismo , Masculino , Fosforilación , Neoplasias de la Próstata/tratamiento farmacológico , Factor de Transcripción STAT3/genética
19.
Int J Clin Oncol ; 26(3): 461-484, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33387088

RESUMEN

Cryoablation (CA), high-intensity focused ultrasound (HIFU), irreversible electroporation (IRE), and vascular-targeted photodynamic therapy (VTP) have been evaluated as novel strategies for selected patients with prostate cancer (PCa). We aim to determine the current status of literature regarding the clinical outcomes among these minimally invasive therapies. A systematic search of PubMed, EMBASE, and the Cochrane Library for all English literature published from January 2001 to December 2019 was conducted to identify studies evaluating outcomes of CA, HIFU, IRE or VTP on PCa. Proportionality with 95% confidence intervals (CIs) was performed using STATA version 14.0. 56 studies consisting of 7383 participants were found to report data of interest and fulfilled the inclusion criteria in the final meta-analysis. The pooled proportions of positive biopsy after procedure were 20.0%, 24.3%, 24.2%, and 36.2% in CA, HIFU, IRE and VTP, respectively. The pooled proportions of BRFS were 75.7% for CA and 74.4% for HIFU. The pooled proportions of CSS were 96.1%, 98.2%, and 97.9% for CA, HIFU, and IRE, respectively. The pooled proportions of OS were 92.8% for CA and 85.2% for HIFU. The pooled proportions of FFS were 64.7%, 90.4%, and 76.7% for CA, IRE and VTP, respectively. The pooled proportions of MFS were 92.8% for HIFU and 99.1% for IRE. This meta-analysis shows that CA, HIFU, IRE, and VTP are promising therapies for PCa patients with similar clinical outcomes. However, further larger, well-designed randomized controlled trials are required to confirm this assertion.


Asunto(s)
Criocirugia , Fotoquimioterapia , Neoplasias de la Próstata , Biopsia , Electroporación , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Resultado del Tratamiento
20.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451122

RESUMEN

BACKGROUND: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. METHODS: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10-6 M) and bicalutamide (BCT) (10-4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-ß (ERß), respectively. RESULTS: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERß mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. CONCLUSION: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERß expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.


Asunto(s)
Hormonas/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Neoplasias de la Próstata/metabolismo , Transducción de Señal/efectos de los fármacos , Esteroides/metabolismo , Tadalafilo/farmacología , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Transporte de Proteínas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
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