title: The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication.
abstract: 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 α to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon α on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFNα 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 IFNα-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFNα-dependent PKR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFNα-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon α 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 α-dependent antiviral response.
authors.affiliation: Paul-Ehrlich-Institute, Division of Virology, Langen, Germany.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Himmelsbach
authors.forename: Eberhard
authors.initials: E
authors.lastname: Hildt
mesh_terms: D000998:Antiviral Agents / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf