Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Nat Prod ; 84(7): 2004-2011, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34225450

RESUMO

Malaymycin (1), a new cyclopentenone-containing tetrahydroquinoline alkaloid, and mccrearamycin E (2), a geldanamycin analogue bearing a rare ring-contracted cyclopentenone moiety, and a C2-symmetric macrodiolide (7) were isolated from Streptomyces malaysiensis SCSIO41397. Their structures including absolute configurations were determined by detailed analyses of NMR and HRMS data and ECD calculations. The occurrence of mccrearamycin E (2) bearing a ring-contracted cyclopentenone is rare in the geldanamycin class. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1, 4, 5, and 7 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.067 to 7.2 µM. In particular, compound 1 inhibited the growth of C42B and H446 cell lines with IC50 values of 67 and 70 nM, respectively. Malaymycin (1) significantly induced cell cycle arrest at the G0/G1 phase in C42B cell lines and caused cell shrinkage and inhibited the expression of the androgen receptor (AR) at both the mRNA and protein levels in a dose-dependent manner. Further examination by qRT-PCR analysis showed that 1 strongly suppressed the expression of AR target genes KLK2 and KLK3 in the C42B and 22RV1 cell lines, which suggested that 1 might be a promising potential lead compound for the development of a treatment for the castration-resistant prostate cancer (CRPC).


Assuntos
Alcaloides/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Benzoquinonas/farmacologia , Ciclopentanos/farmacologia , Lactamas Macrocíclicas/farmacologia , Quinolinas/farmacologia , Streptomyces/química , Alcaloides/isolamento & purificação , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Animais , Benzoquinonas/isolamento & purificação , Linhagem Celular Tumoral , China , Ciclopentanos/isolamento & purificação , Humanos , Lactamas Macrocíclicas/isolamento & purificação , Masculino , Estrutura Molecular , Poríferos/microbiologia , Neoplasias de Próstata Resistentes à Castração , Quinolinas/isolamento & purificação , Receptores Androgênicos
2.
Nutrients ; 9(10)2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28953224

RESUMO

Benign prostatic hyperplasia (BPH) is characterized by uncontrolled proliferation of the prostate gland. Cynanchum wilfordii has been reported to improve sexual behavior in male rats. In this study, we investigated the protective effect of an aqueous extract of C. wilfordii (CWW) against BPH development in a testosterone-induced BPH rat model. The rats were divided into the following six groups: sham/vehicle; BPH/vehicle; BPH/finasteride; and three CWW doses (50, 100, and 200 mg/kg). After a 4-week treatment with CWW, the rats were euthanized at scheduled times, and their prostates were weighed, followed by a histopathological examination. Prostate growth inhibition rates in rats administered CWW 50, 100, and 200 mg/kg were 54.5%, 51.8%, and 50.1%, respectively. The BPH/CWW group showed decreased serum testosterone and dihydrotestosterone (DHT) levels compared to the BPH/vehicle group. Furthermore, the BPH/CWW group showed reduced prostate testosterone and DHT levels compared to the BPH/vehicle group. Mechanistically, the reverse transcription-polymerase chain reaction revealed downregulated mRNA expression levels of the androgen receptor, 5α-reductase, and B-cell lymphoma-2 (Bcl-2) in the BPH/CWW200 group compared with those in the testosterone-induced groups. In conclusion, these findings show the effectiveness of CWW in slowing the progression of testosterone-induced BPH in rats.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cynanchum , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/prevenção & controle , Receptores Androgênicos/efeitos dos fármacos , Testosterona , Inibidores de 5-alfa Redutase/isolamento & purificação , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Animais , Colestenona 5 alfa-Redutase/genética , Cynanchum/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Tamanho do Órgão , Extratos Vegetais/isolamento & purificação , Raízes de Plantas , Próstata/enzimologia , Próstata/patologia , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores de Tempo
3.
J Antibiot (Tokyo) ; 70(5): 595-600, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28174422

RESUMO

Castration-resistant prostate cancer (CRPC) is the most aggressive form of this disease. CRPC remains dependent on androgen receptor (AR) signaling. Therefore, a novel AR antagonist, enzalutamide, is used clinically for the treatment of men with metastatic CRPC. However, enzalutamide-resistant AR has appeared, and a new type of AR antagonist is desired. Previously, in the course of screening for a new type of AR antagonist, we isolated a series of compounds, designated antarlides A-E, that share a novel 22-membered-ring macrocyclic structure and are produced by Streptomyces sp. BB47. In the present study, we found that this strain also produces antarlides F-H as minor components. Antarlide F is a novel geometric isomer of known antarlides. On the other hand, antarlides G and H are new members of the antarlide family that have a 20-membered-ring macrocyclic structure. Antarlides G and H inhibited the binding of androgen to AR in vitro at concentrations similar to those observed with antarlides A-E. In addition, antarlide G inhibited the transcriptional activity of not only wild-type AR but also enzalutamide-resistant AR, suggesting that antarlides with either 22- or 20-membered rings may serve as potent third-generation AR antagonists capable of overcoming resistance to enzalutamide.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Compostos Macrocíclicos/farmacologia , Feniltioidantoína/análogos & derivados , Streptomyces/metabolismo , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/isolamento & purificação , Masculino , Nitrilas , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
4.
J Antibiot (Tokyo) ; 68(4): 279-85, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25269460

RESUMO

Androgen receptor (AR) is a validated target in all clinical states of prostate cancer. Androprostamines A and B, the new inhibitors of androgen receptor, were isolated from Streptomyces sp. MK932-CF8. Their structures were determined by the spectroscopic analysis, degradation studies and synthesis. Androprostamines showed potent inhibitory effect against androgen-dependent growth of human prostate cancer cells without cytotoxicity and repressed the androgen-induced expression of AR-regulated genes.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Streptomyces/metabolismo , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética
5.
PLoS One ; 8(8): e72472, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24015248

RESUMO

Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MS(n) experiments elucidated the molecule's structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MS(n) data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome.


Assuntos
Antagonistas de Receptores de Andrógenos/análise , Água Potável/análise , Disruptores Endócrinos/análise , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Antagonistas de Receptores de Andrógenos/farmacologia , Bioensaio , Disruptores Endócrinos/isolamento & purificação , Disruptores Endócrinos/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Fumaratos/análise , Fumaratos/isolamento & purificação , Fumaratos/farmacologia , Genes Reporter , Humanos , Concentração Inibidora 50 , Maleatos/análise , Maleatos/isolamento & purificação , Maleatos/farmacologia , Receptores Androgênicos/metabolismo , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Ativação Transcricional/efeitos dos fármacos , Leveduras
6.
Phytother Res ; 26(5): 669-74, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21997969

RESUMO

Our group previously reported that tanshinone IIA induced apoptosis via a mitochondria dependent pathway in LNCaP prostate cancer cells. In the present study, the roles of androgen receptor (AR) and p53 signaling pathways were investigated in tanshinone IIA-induced G1 arrest in LNCaP cells. Tanshinone IIA significantly inhibited the growth and proliferation of LNCaP cells by colony formation and BrdU incorporation assays, respectively. Tanshinone IIA induced cell cycle arrest at G1 phase and down-regulated cyclin D1, CDK2 and CDK4. Furthermore, tanshinone IIA activated the phosphorylation of p53 at Ser 15 residue and its downstream p21 and p27. Additionally, tanshinone IIA suppressed the expression of AR and prostate specific antigen (PSA). Conversely, silencing p53 using its specific siRNA reversed cyclin D1 expression inhibited by tanshinone IIA. However, knockdown of AR had no effect on the p53/p21/p27 signaling pathway activated by tanshinone IIA in LNCaP cells. In AR siRNA-transfected cells, tanshinone IIA did not cause cell cycle arrest and reduce cyclin D1, implying that AR is essential to induce G1 arrest by tanshinone IIA in LNCaP cells. Taken together, the findings suggest that tanshinone IIA induces G1 arrest via activation of p53 signaling and inhibition of AR in LNCaP cells.


Assuntos
Abietanos/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Receptores Androgênicos/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Abietanos/química , Abietanos/isolamento & purificação , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Raízes de Plantas/química , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , RNA Interferente Pequeno , Receptores Androgênicos/metabolismo , Salvia miltiorrhiza/química , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
7.
Cancer Res ; 71(4): 1208-13, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21285252

RESUMO

Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). Mounting evidence supports the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). All current therapies that target the AR are dependent on the presence of its C-terminal ligand-binding domain (LBD). However, it is the N-terminal domain (NTD) of the AR that is the "Achilles' heel" of AR activity, with AF-1 being essential for AR activity regardless of androgen. Recent efforts to develop drugs to the AR NTD have yielded EPI-001, a small molecule, sintokamide peptides, and decoys to the AR NTD with EPI-001, the best characterized and most promising for clinical development based upon specificity, low toxicity, and cytoreductive antitumor activity.


Assuntos
Antagonistas de Receptores de Andrógenos/isolamento & purificação , Antagonistas de Receptores de Andrógenos/uso terapêutico , Carcinoma/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/cirurgia , Humanos , Masculino , Modelos Biológicos , Orquiectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/genética , Bibliotecas de Moléculas Pequenas/análise , Falha de Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...