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1.
Biosci Rep ; 41(5)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33974005

RESUMO

Androgen deprivation therapy (ADT) is one of the typical treatments used for patients with prostate cancer (PCa). ADT, however, may fail when PCa develops castration-resistance. Fatty acid synthase (FASN), a critical enzyme involved in fatty acid synthesis, is found to be up-regulated in PCa. Since enzalutamide and ADT are frequently used for the treatment of PCa, the present study aimed to unravel the underlying mechanism of combination of orlistat, an FASN inhibitor, and enzalutamide using PC3 cell line; and orlistat and castration in PC3 tumor-bearing animal model. Cytotoxicity was determined by AlamarBlue assay. Drug effects on the cell cycle and protein expressions were assayed by the flow cytometry and Western blot. Electromobility shift assay was used to evaluate the NF-κB activity. The tumor growth delay, expressions of the signaling-related proteins, and histopathology post treatments of orlistat and castration were evaluated in PC3 tumor-bearing mouse model. The results showed that orlistat arrested the PC3 cells at the G1 phase of the cell cycle and enhanced the cytotoxic effects of enzalutamide synergistically. Pretreatment with orlistat combined with castration inhibited the tumor growth significantly compared with those of castration and orlistat treatments alone in PC3 tumor-bearing mice. Combination treatment reduced both FASN and NF-κB activities and their downstream effector proteins. The present study demonstrated the synergistic effects of orlistat combined with enzalutamide in vitro and castration in vivo on human PCa.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Nitrilas/uso terapêutico , Orlistate/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintase Tipo I/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Nitrilas/farmacologia , Orquiectomia/métodos , Orlistate/toxicidade , Células PC-3 , Feniltioidantoína/farmacologia , Neoplasias da Próstata/cirurgia
2.
Sci Rep ; 10(1): 1499, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001767

RESUMO

Many mosquito transmitted viruses of the genera Alphavirus and Flavivirus are human pathogens of significant concern, and there is currently no specific antiviral for any member of these two genera. This study sought to investigate the broad utility of orlistat (tetrahydrolipstatin) in reducing virus infection for several mosquito borne viruses including flaviviruses (dengue virus (DENV; nine isolates analyzed), Japanese encephalitis virus (JEV; one isolate analyzed) and Zika virus (ZIKV; 2 isolates analyzed)) as well as an alphavirus (chikungunya virus; CHIKV; 2 isolates analyzed). Three different treatment regimens were evaluated, namely pre-treatment (only), post-treatment (only) and pre- and post-treatment, and three factors were evaluated, namely level of infection, virus titer and genome copy number. Results showed that all three treatment modalities were able to significantly reduce virus titer for all viruses investigated, with the exception of three isolates of DENV in the pre-treatment only regimen. Pre- and post-treatment was more effective in reducing the level of infection and genome copy number of all viruses investigated than either pre-treatment or post-treatment alone. Collectively, these results suggest orlistat has potential as a broad-spectrum agent against multiple mosquito transmitted viruses.


Assuntos
Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Orlistate/farmacologia , Zika virus/efeitos dos fármacos , Animais , Antivirais/toxicidade , Linhagem Celular , Vírus Chikungunya/genética , Vírus Chikungunya/fisiologia , Vírus da Dengue/genética , Vírus da Dengue/fisiologia , Vírus da Encefalite Japonesa (Espécie)/genética , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Dosagem de Genes/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Genoma Viral/efeitos dos fármacos , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Orlistate/toxicidade , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacos , Zika virus/genética , Zika virus/fisiologia
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