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1.
Toxicol Appl Pharmacol ; 401: 115102, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512071

RESUMO

PURPOSE: Cadmium (Cd) is reported to be associated with carcinogenesis. The molecular mechanisms associated with Cd-induced prostate cancer (PCa) remain elusive. MATERIALS AND METHODS: RWPE1, PWR1E and DU 145 cells were used. RT2 Profiler Array, real-time-quantitative-PCR, immunofluorescence, cell cycle, apoptosis, proliferation and colony formation assays along with Gene Set Enrichment Analysis (GSEA) were performed. RESULT: Chronic Cd exposure of non-malignant RWPE1 and PWR1E cells promoted cell survival, proliferation and colony formation with inhibition of apoptosis. Even a two-week Cd exposure of PCa cell line (DU 145) significantly increased the proliferation and decreased apoptosis. RT2 profiler array of 84 genes involved in the Erk/MAPK pathway revealed induction of gene expression in Cd-RWPE1 cells compared to RWPE1. This was confirmed by individual TaqMan gene expression analysis in both Cd-RWPE1 and Cd-PWR1E cell lines. GSEA showed an enrichment of the Erk/MAPK pathway along with other pathways such as KEGG-ERBB, KEGG-Cell Cycle, KEGG-VEGF, KEGG-Pathways in cancer and KEGG-prostate cancer pathway. We randomly selected upregulated genes from Erk/MAPK pathway and performed profile analysis in a PCa data set from the TCGA/GDC data base. We observed upregulation of these genes in PCa compared to normal samples. An increase in phosphorylation of the Erk1/2 and Mek1/2 was observed in Cd-RWPE1 and Cd-PWR1E cells compared to parental cells, confirming that Cd-exposure induces activation of the Erk/MAPK pathway. CONCLUSION: This study demonstrates that Erk/MAPK signaling is a major pathway involved in Cd-induced malignant transformation of normal prostate cells. Understanding these dominant oncogenic pathways may help develop optimal therapeutic strategies for PCa.


Assuntos
Cádmio/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Próstata/efeitos dos fármacos , Próstata/enzimologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/enzimologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Próstata/patologia , Neoplasias da Próstata/patologia
2.
Prostate ; 80(12): 938-949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542667

RESUMO

BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.


Assuntos
Interleucina-8/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores CXCR/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Humanos , Interleucina-8/biossíntese , Interleucina-8/genética , Masculino , Ácido Oleanólico/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/biossíntese , Receptores CXCR/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
3.
Exp Mol Pathol ; 115: 104473, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32454105

RESUMO

The aim of this study was to evaluate the impact of prenatal testosterone exposure on prostate development in male and female neonatal gerbils. Pregnant females were exposed to subcutaneous injections of testosterone cypionate (500 µg/animal) at gestational days 20 and 22. Male and female pups were then euthanized at postnatal day 1. Morphological analysis showed that females were severely affected by androgen exposure. We also observed that male and female urogenital sinus (UGS) responded differentially to testosterone treatment, demonstrating heterogeneous immunostaining for the androgen receptor (AR), estrogen receptor alpha (ERα), and proliferating cell nuclear antigen (PCNA). Smooth muscle α-actin (α-SMA) analysis showed that testosterone delays the myodifferentiation, allowing buds to reach the ectopic mesenchymes of the female UGS. Our data showed that abnormal testosterone exposure disrupted prostate organogenesis, altered the expression patterns of important markers, and demonstrated that female UGS was particularly influenced by androgen exposure during a critical window in the developmental period.


Assuntos
Organogênese/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Testosterona/farmacologia , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Gerbillinae , Imageamento Tridimensional , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/anatomia & histologia , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Testosterona/sangue
4.
Prostate ; 80(11): 831-849, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449814

RESUMO

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.


Assuntos
Integrina alfa2beta1/antagonistas & inibidores , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Dipeptídeos/farmacologia , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Piperazinas/farmacologia , Próstata/metabolismo , Próstata/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Tromboxano A2/metabolismo , Vasoconstritores/farmacologia
5.
Braz J Med Biol Res ; 53(5): e9108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321149

RESUMO

Recent evidence suggests that aerobic physical training may attenuate the deleterious effects of cancer risk factors, including smoking. We investigated the effects of cigarette smoke inhalation and aerobic physical training on the expression of steroid receptors and inflammatory and apoptotic proteins in the prostate. Forty male Wistar rats were distributed in four groups: control (CO), exercise (EXE), cigarette smoke exposure (CS), and cigarette smoke exposure with exercise (CS+EXE). For eight weeks, animals were repeatedly exposed to cigarette smoke for 30 min or performed aerobic physical training either with or without the cigarette smoke inhalation protocol. Following these experiments, we analyzed prostate epithelial morphology and prostatic expression of androgen (AR) and glucocorticoid receptors (GR), insulin-like growth factor (IGF-1), B-cell lymphoma-2 (BCL-2), BCL-2-associated X protein (BAX), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) via immunohistochemistry. Cigarette smoke exposure stimulated the expression of AR, IGF-1, BCL-2, and NF-κB while downregulating BAX, IL-6, and TNF-α labeling in the prostate. In contrast, aerobic physical training attenuated cigarette smoke-induced changes in AR, GR, IGF-1, BCL-2, IL-6, TNF-α, and NF-κB. This suggests that cigarette smoke stimulates inflammation and reduces apoptosis, culminating in increased prostatic epithelial and extracellular matrices, whereas physical training promoted beneficial effects towards maintaining normal prostate morphology and protein levels.


Assuntos
Biomarcadores/análise , Condicionamento Físico Animal , Próstata/patologia , Fumaça/efeitos adversos , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Inflamação , Masculino , Próstata/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo
6.
Nat Commun ; 11(1): 1987, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332823

RESUMO

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.


Assuntos
Próstata/patologia , Hiperplasia Prostática/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Biomarcadores/análise , Metilação de DNA , Epigênese Genética , Epigenômica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Medicina de Precisão/métodos , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Agentes Urológicos/farmacologia , Sequenciamento Completo do Genoma
7.
Genes Cells ; 25(7): 450-465, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277721

RESUMO

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5' TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0 /G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0 /G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.


Assuntos
Androgênios/toxicidade , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/metabolismo , Instabilidade Genômica/genética , Diester Fosfórico Hidrolases/metabolismo , Próstata/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quebra Cromossômica , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/genética , Proteínas de Ligação a DNA/genética , Células Epiteliais/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Instabilidade Genômica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Próstata/efeitos dos fármacos , Neoplasias da Próstata/genética , RNA Interferente Pequeno , Receptores Androgênicos/metabolismo
8.
Am J Physiol Renal Physiol ; 318(3): F754-F762, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036697

RESUMO

Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome c oxidase subunit 2, transforming growth factor-ß1, interleukin-1ß, hypoxia-inducible factor-1α, α1A-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca2+ channel subunit-α1D, neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-ß1, interleukin-1ß, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.


Assuntos
Prostatite/induzido quimicamente , Doenças Uretrais/etiologia , Animais , Citocinas/genética , Citocinas/metabolismo , Formaldeído/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Próstata/efeitos dos fármacos , Próstata/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Food Funct ; 11(2): 1547-1559, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003372

RESUMO

Aging and overweight are involved in prostatic lesion development, due to their association with cell proliferation, hormonal imbalance and angiogenesis. The jaboticaba fruit is rich in bioactive compounds, showing potential chemopreventive action such as the capacity to modulate hormones and angiogenesis hallmarks. This study aimed to evaluate the jaboticaba extract (PJE) effect on the prostate morphology and on molecules related to hormone signaling and angiogenesis, during aging and/or high-fat diet (HFD) intake. Seventy FVB mice were distributed into experimental groups: YG group (young: 3 month old mice), AG group (aged: 11 month old mice), HfAG group (aged + HFD), JAGI group (aged + 2.9 g kg-1 PJE), JAGII group (aged + 5.8 g kg-1 PJE), HfJAGI group (aged + HFD + 2.9 g kg-1 PJE) and HfJAGII group (aged + HFD + 5.8 g kg-1 PJE). The ventral prostate was collected for morphological, immunohistochemistry and western-blotting analysis after 60 days of treatment. All PJE treatments promoted hormonal signaling balance and inhibited angiogenesis in the prostates of aged or HFD-fed aged mice, leading to the maintenance of healthy prostate morphology. A high dose of the PJE (JAGII and HfJAGII groups) led to the best capacity to reduce AR (58.40% and 74.42%; p = 0.0240 and p = 0.0023), ERα (30.29% and 45.12%; p = 0.0004 and p < 0.0001), aromatase (39.54% and 55.94%; p = 0.0038 and p = 0.0020), and VEGF (50.81% and 67.68%; p < 0.0001) and increase endostatin immunoexpression. Moreover, HFD intake intensified the hormonal and angiogenic alterations in the aged mouse prostates, contributing to the increase in premalignant lesion incidence. The PJE exerted a dose-dependent positive effect on aged or HFD-fed aged mouse prostates, contributing to the gland microenvironment recovery, mainly due to the hormonal and angiogenic balance. Therefore, we suggest that the PJE can be a potential candidate for prostatic lesion prevention.


Assuntos
Envelhecimento/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Myrtaceae/química , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Masculino , Camundongos
10.
Food Funct ; 11(2): 1585-1598, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003376

RESUMO

Benign prostatic hyperplasia (BPH) is a common chronic disease in aging men. The present study aimed to identify the active fraction of a purple rice extract and determine its anti-prostatic hyperplasia effect in a testosterone implanted rat model. The hexane insoluble fraction (HIF) which mainly contains hydrophilic phytochemicals from the purple rice crude ethanolic extract was defined as the active fraction, due to a potent effect on the downregulation of androgen receptor (AR) expression in malignant prostate cells, in addition to low toxicity for normal fibroblast cells. To induce BPH, subcutaneous implanting of a testosterone containing tube was performed in the castrated rats. Oral administration of HIF of at least 0.1 g kg-1 retarded prostate enlargement and improved histological changes induced by testosterone, without any effects on the serum testosterone levels. A lower proliferating cell nuclear antigen (PCNA) labelling index and the downregulated expression of AR, cyclinD1, and fatty acid synthase were clearly observed in the prostates of HIF-fed rats. Additionally, the mRNA levels of inflammation-related cytokines and enzymes in the prostate tissues significantly decreased after HIF treatment. Taken together, these findings demonstrate molecular mechanisms underlying the potential protective effects of the purple rice active fraction against testosterone-induced BPH in rats.


Assuntos
Oryza/química , Extratos Vegetais/farmacologia , Próstata , Hiperplasia Prostática/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Células NIH 3T3 , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Ratos , Ratos Wistar , Testosterona
11.
Nat Commun ; 11(1): 384, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959826

RESUMO

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


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumores Neuroendócrinos/genética , Neoplasias da Próstata/genética , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Mol Life Sci ; 77(22): 4663-4673, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31894360

RESUMO

The androgen receptor (AR) plays an important role in the pathogenesis and development of prostate cancer (PCa). Mostly, PCa progresses to androgen-independent PCa, which has activated AR signaling from androgen-dependent PCa. Thus, inhibition of AR signaling may be an important therapeutic target in androgen-dependent and castration-resistant PCa. In this study, we determined the anticancer effect of a newly found natural compound, sakurasosaponin (S-saponin), using androgen-dependent and castration-resistant PCa cell lines. S-saponin induces mitochondrial-mediated cell death in both androgen-dependent (LNCaP) and castration-resistant (22Rv1 and C4-2) PCa cells, via AR expression. S-saponin treatment induces a decrease in AR expression in a time- and dose-dependent manner and a potent decrease in the expression of its target genes, including prostate-specific antigen (PSA), transmembrane protease, serin 2 (TMPRSS2), and NK3 homeobox 1 (NKX3.1). Furthermore, S-saponin treatment decreases B-cell lymphoma-extra large (Bcl-xL) and mitochondrial membrane potential, thereby increasing the release of cytochrome c into the cytosol. Moreover, Bcl-xL inhibition and subsequent mitochondria-mediated cell death caused by S-saponin were reversed by Bcl-xL or AR overexpression. Interestingly, S-saponin-mediated cell death was significantly reduced by a reactive oxygen species (ROS) scavenger, N-acetylcystein. Animal xenograft experiments showed that S-saponin treatment significantly reduced tumor growth of AR-positive 22Rv1 xenografts but not AR-negative PC-3 xenografts. Taken together, for the first time, our results revealed that S-saponin induces mitochondrial-mediated cell death in androgen-dependent and castration-resistant cells through regulation of AR mechanisms, including downregulation of Bcl-xL expression and induction of ROS stress by decreasing mitochondrial membrane potential.


Assuntos
Antineoplásicos/envenenamento , Morte Celular/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Saponinas/farmacologia , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Nus , Células PC-3 , Próstata/efeitos dos fármacos , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína bcl-X/metabolismo
13.
Nutrients ; 12(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935838

RESUMO

BACKGROUND: Zinc (Zn) and selenium (Se) play a well-documented role in cancer prevention (e.g., for prostate cancer), and their combined supplementation is often given as a recommended prophylactic agent. The aim of the study was to determine the influence of Zn and/or Se supplementation on the androgen receptor (AR) in the prostate lobes and the serum selected hormone concentrations; a hitherto unresearched topic. METHODS: Male rats (n = 84) were administered with Zn and/or Se intragastrically for up to 90 days. The effects of administration on the tested parameters were checked after 30 and 90 days of administration and additionally, 90 days after the end of 90 day administration. RESULTS: Zn alone leads to an increase in serum testosterone concentrations, while the protein expression of AR in both parts of the prostate increases. Combined administration of Zn and Se eliminates the effect of Zn, which may suggest that these two elements act antagonistically. Se supplementation alone results in the same level of AR protein expression in administration and 90 days after administration periods. CONCLUSION: This paper presents the first report of the influence of Zn and/or Se supplementation on the protein expression of AR in the prostate. Our findings seem to indicate that simultaneous supplementation of both elements may be ineffective.


Assuntos
Suplementos Nutricionais , Interações Medicamentosas , Próstata/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Selênio/farmacologia , Testosterona/sangue , Zinco/farmacologia , Animais , Hormônios/sangue , Masculino , Próstata/metabolismo , Ratos Wistar
14.
Sci Rep ; 10(1): 986, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969640

RESUMO

Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-PCD) in prostate cancer cell lines, PC-3 and DU 145, respectively. Cell homeostasis disruption was demonstrated upon treatment, as shown by the increase in calcium ion through colourimetric assay and endoplasmic reticulum (ER) stress markers GRP 78 and p-eIF2α through western blot. Subsequently, cytoplasmic death protease calpain-2 also showed increased activity during DMDP-1 & -2 treatments, while lysosomic death protease cathepsin B activity was significantly increased in PC-3 treated with DMDP-1. Flow cytometry showed a reduction in mitochondrial membrane potential in both cell lines, while western blotting showed translocation of mitochondrial death protease AIF into the cytoplasm in its truncated form. Furthermore, DMDP-1 & -2 treatments caused significant increase in superoxide level and oxidative DNA damage. Concurrent inhibition of calpain-2 and cathepsin B during the treatment showed an attenuation of cell death in both cell lines. Hence, DMDP-1 & -2 induce CI-PCD in prostate cancer cell lines through calpain-2 and cathepsin B.


Assuntos
Calpaína/metabolismo , Catepsina B/metabolismo , Morte Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Magnoliopsida , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
15.
Sci Rep ; 10(1): 980, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969643

RESUMO

Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipogenic signaling and suppression of lipid metabolic pathways. The expression of proteins responsible for lipogenesis was down regulated. The membrane permeability and functionality of PCa were severely affected and caused nuclear disorganization during drug exposure. Finally, these consolidated events shifted the cell's survival balance towards apoptosis. These results suggest that TA distinctly interferes with the lipid signaling and metabolism of PCa cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taninos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
BMJ Open ; 10(1): e033667, 2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31988233

RESUMO

INTRODUCTION: Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer. METHODS AND ANALYSIS: The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis. ETHICS AND DISSEMINATION: The protocol was approved by a central ethics review committee (St Vincent's Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY: Novartis. PROTOCOL VERSION: 2.0, 30 May 2019 TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).


Assuntos
Aminopiridinas/farmacologia , Terapia Neoadjuvante , Próstata/efeitos dos fármacos , Prostatectomia , Neoplasias da Próstata , Purinas/farmacologia , Adolescente , Adulto , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Caspase 3/metabolismo , Ciclo Celular , Proliferação de Células , Ensaios Clínicos Fase II como Assunto , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Fatores de Transcrição E2F/metabolismo , Humanos , Calicreínas , Masculino , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Purinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
18.
Toxicol Lett ; 319: 1-10, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689472

RESUMO

Chlorocholine chloride (CCC), a plant growth retardant, may act as an endocrine disruptor. Our previous study showed that pubertal CCC exposure in rats might decrease testosterone (T) synthesis. This study observed the changes in pubertal development and reproduction of male rats exposed to CCC and its underlying mechanisms. Rats were exposed to CCC (0, 75, 137.5 and 200 mg/kg bw/day) from postnatal day 23 to 60. The results showed that CCC treatment delayed the onset of puberty and reduced the relative organ weight of prostate. Seminiferous tubules with deciduous spermatogenic cells were observed in the 200 mg/kg bw/day group. Sexual behavior was inhibited in the 137.5 and 200 mg/kg bw/day groups. Sperm motility, litter size and normalized anogenital distance (AGD) of male pups were decreased in the 137.5 and 200 mg/kg bw/day groups. Serum kisspeptin level and serum and testicular levels of T were reduced in all CCC treated groups. Crucial hormones in hypothalamic-pituitary-testicular (HPT) axis were reduced subsequently after CCC treatment. Collectively, our results demonstrated that CCC might disturb HPT axis through suppressing the secretion of kisspeptin and subsequently lead to delayed puberty onset and impaired reproductive functions.


Assuntos
Clormequat/toxicidade , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Genitália/anatomia & histologia , Genitália/efeitos dos fármacos , Genitália/crescimento & desenvolvimento , Hormônios Esteroides Gonadais/sangue , Kisspeptinas/metabolismo , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/sangue
19.
J Urol ; 203(5): 940-948, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31845837

RESUMO

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


Assuntos
Androstenodiona/farmacologia , Castração/métodos , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/terapia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Testosterona/farmacologia , Anabolizantes/farmacologia , Androgênios/farmacologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Seguimentos , Humanos , Masculino , Espectrometria de Massas , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/efeitos dos fármacos , Fatores de Tempo
20.
Environ Toxicol ; 35(1): 15-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31454150

RESUMO

The prostate is an accessory reproductive gland that is sensitive to the action of exogenous compounds known as endocrine disrupters that alter normal hormonal function. Finasteride is a widely used chemical that acts to inhibit the conversion of testosterone in its most active form, dihydrotestosterone. It is known that intrauterine exposure to finasteride causes changes in the male prostate even at low dosages; however, it is not known whether these dosages are capable of causing changes in the female prostate, which is present in a large number of mammalian species, including humans. In the present study, histochemistry, immunohistochemistry, immunofluorescence, serological dosages, and three-dimensional reconstruction techniques were employed to evaluate the effects of intrauterine exposure to a low dose of finasteride (100 µg.BW/d) on postnatal prostate development in male and female Mongolian gerbils. The results indicate that the gerbil female prostate also undergoes alterations following intrauterine exposure to finasteride, exhibiting a thickening of periductal smooth muscle and increased stromal proliferation. There are also intersex differences in the impact of exposure on the expression of the androgen receptor, which was increased in males, and of the estrogen-α receptor, which was decreased in the male prostate but unchanged in females. Altogether, this study indicates there are sex differences in the effects of finasteride exposure even at low dosages.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Finasterida/toxicidade , Genitália Feminina/efeitos dos fármacos , Gerbillinae/embriologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Próstata/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Genitália Feminina/embriologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Próstata/embriologia , Receptores Androgênicos/metabolismo , Reprodução/efeitos dos fármacos , Testosterona/metabolismo
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