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Toxicol In Vitro ; 60: 420-436, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31175925

RESUMO

Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC50 value of 60 µM and 66 µM, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Glutationa/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fase S/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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