YC-1 induces apoptosis of human renal carcinoma A498 cells in vitro and in vivo through activation of the JNK pathway.

摘要: Background and purpose: The aim of this study was to elucidate the mechanism YC-1{3-(5′-hydroxy methyl-2′-furyl)-1-benzylindazole}-induced human renal carcinoma cells apoptosis evaluate potency YC-1 in models tumour growth mice. Experimental approach: YC-1-mediated assessed by analysis MTT, SRB, DAPI staining flow cytometry analysis. Knockdown JNK protein achieved transient transfection using siRNA. The mechanisms action on different signalling pathways involved were studied western blot. Fas clustering analysed confocal microscopy vivo efficacy examined a A498 xenograft model. Key results: YC-1 displayed cytotoxicity at 10−7–10−8 M. Increased condensation chromatin observed an increase cell population subG1 phase. Moreover, triggered mitochondria-mediated caspase-dependent pathways. significantly induced ligand expression, but did not modify either levels death receptors or ligands. In addition, responsive observed, suggesting involvement Fas-mediated pathway. Furthermore, markedly phosphorylation inhibitor, SP600125, siRNA JNK1/2 reversed YC-1-induced expression. We suggest that phosphorylation, upregulation FasL receptor promote activation caspases 8 3, resulting apoptosis. Finally, we demonstrated antitumour effect vivo. Conclusions implications: These data is good candidate for development as anticancer drug. British Journal Pharmacology (2008) 155, 505–513; doi:10.1038/bjp.2008.292; published online 21 July 2008