The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication
The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication
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DOI：
10.1016/j.ejcb.2012.09.001
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发表时间：
2013-01-01
影响因子：
6.6
通讯作者：
Hildt, Eberhard
中科院分区：
文献类型：
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作者：
Himmelsbach, Kiyoshi;Hildt, Eberhard
最近，研究表明激酶抑制剂索拉非尼通过抑制 c-Raf 有效阻断 HCV 复制。然而，使用较高剂量的索拉非尼进行较长时间的治疗可能会产生不良反应。因此，我们分析了是否可以减少索拉非尼的剂量与干扰素α联合应用以获得附加抗病毒作用，同时减少不良反应。然而，索拉非尼消除了干扰素α对HCV复制的抑制作用，反之亦然。为了揭示潜在机制，我们观察到一方面IFNα激活c-Raf，从而抵消索拉非尼对HCV复制的抑制作用，这种抑制作用基于索拉非尼依赖性c-Raf抑制。另一方面我们发现IFNα诱导的PKR磷酸化依赖于c-Raf。因此，索拉非尼作为 c-Raf 的有效抑制剂可防止 IFN α 依赖性 PMR 磷酸化。此外，索拉非尼抑制 c-Raf 独立的 STAT1 磷酸化，导致 IFN α 依赖性基因的诱导受损。综上所述，这些数据表明，联合应用索拉非尼和干扰素α以获得抗病毒作用是没有用的，因为索拉非尼对对于干扰素α依赖性抗病毒反应的转导至关重要的靶点发挥抑制作用。 (C) 2012 爱思唯尔有限公司。版权所有。
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 alpha to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon alpha on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFN alpha 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 alpha-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFN alpha-dependent PMR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFN alpha-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon alpha 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 alpha-dependent antiviral response. (C) 2012 Elsevier GmbH. All rights reserved.