Inhibition of insulin/IGF-1 receptor signaling enhances bile acid toxicity in primary hepatocytes.

摘要: Modulation of ERBB and insulin-like growth factor 1 (IGF-1) receptor function is recognized as a potential mechanism to inhibit tumor growth. We others have shown that inhibition ERBB1 can enhance bile acid toxicity. Herein, we extend our analyses examine the impact insulin/IGF-1 on primary hepatocyte survival when exposed secondary deoxycholic (DCA) compare this has toxicity effects ERBB1/MEK1/2 inhibition. The inhibitor NVP-ADW742 at concentrations which both insulin IGF-1 receptors had modest negative viability, strongly potentiated DCA-induced apoptotic cell death. Identical data were obtained expressing dominant in hepatocytes; acts trans. Inhibition using Iressa (gefitinib) or tyrphostin AG1478 more enhancing DCA lethality than function. In contrast, over-expression protein pleiotropic multiple signaling pathways an apparently non-specific manner. These findings suggest novel therapeutic kinase inhibitors, targeted against receptors, promote flow may be impaired.