Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivoReport as inadecuate




Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo - Download this document for free, or read online. Document in PDF available to download.

Mammalian target of rapamycin mTORin renal cell carcinoma RCC represents a valuable oncotarget for treatment. We here tested the potential anti-RCC activity by a novel mTOR kinase inhibitor WYE-687in vitro and in vivo.WYE-687 was cytotoxic and anti-proliferative to established RCC cell lines 786-O and A498 and primary human RCC cells. Yet, it was non-cytotoxic toHK-2 tubular epithelial cells.WYE-687 provoked caspase-dependent apoptosis in the RCC cells. At the molecular level, WYE-687 almost completely blocked mTORC1 p-S6K1 and p-S6 and mTORC2 p-Akt Ser 473 activation in both 786-Ocells and primary human RCC cells, where it downregulated both hypoxia-inducible factor HIF-1α and HIF-2α expression. Significantly, oral administration of WYE-687 potently suppressed786-O tumor xenograft growth in nude mice. mTORC1-2 activation and HIF-1α-2α expression were also remarkably downregulated in WYE-687-treated tumor tissues. Thus, our preclinical results imply that WYE-687 may have important translational value for the treatment of RCC.



Author: Xiao-dong Pan , Dong-hua Gu , Jia-Hui Mao , Hua Zhu, Xinfeng Chen, Bing Zheng , Yuxi Shan

Source: http://plos.srce.hr/



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