The kinase inhibitor Sorafenib impairs the antiviral effect of interferon ¦Á on hepatitis C virus replication

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• 作者：Kiyoshi Himmelsbach ; Eberhard Hildt ; ^{Eberhard.Hildt@pei.de}
• 关键词：HCV ; hepatitis C virus ; HCC ; hepatocellular carcinoma ; IFN ; interferon ; tdn ; trans dominant negative ; RBV ; ribavirin ; OAS ; oligoadenylate synthase ; PKR ; protein kinase R
• 刊名：European Journal of Cell Biology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：92
• 期：1
• 页码：12-20
• 全文大小：1320 K

文摘

Recently, it was shown that the kinase inhibitor Sorafenib efficiently blocks HCV replication by inhibition of c-Raf. However, a longer treatment with higher doses of Sorafenib might be associated with adverse effects. Therefore, it was analysed whether a decreased dose of Sorafenib can be applied in combination with interferon ¦Á to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon ¦Á on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFN¦Á activates c-Raf and thereby counteracts the inhibitory effect of Sorafenib on HCV replication that is based on the Sorafenib-dependent inhibition of c-Raf. On the other hand we found that the IFN¦Á-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFN¦Á-dependent PKR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFN¦Á-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon ¦Á in order to obtain an antiviral effect is not useful since Sorafenib exerts an inhibitory effect on targets that are crucial for the transduction of interferon ¦Á-dependent antiviral response.