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Liver Cancer Drug Sorafenib (Nexavar) Inhibits Hepatitis C Virus Replication in Laboratory Study

SUMMARY: The chemotherapy drug sorafenib (Nexavar), which was approved in 2007 for the treatment of hepatocellular carcinoma (HCC) also appears to have a direct suppressive effect on hepatitis C virus (HCV) replication, according to the results of a study published in the December 2009 issue of Gut.

By Liz Highleyman

Over years or decades, chronic hepatitis C can lead to advanced liver disease, including cirrhosis and HCC. HCV infection is among the leading causes of liver cancer, transplantation, and liver-related mortality.

Some prior research indicated that the HCV non-structural protein NS5A interacts with a human cellular protein called c-Raf that plays a role in cell signaling and may contribute to the development of cancer.

To further explore this association, a team of German and French researchers undertook a study to assess whether sorafenib -- an inhibitor of c-Raf -- might suppress HCV replication.

In this laboratory study, HuH7.5 cells containing replicating HCV were exposed to sorafenib. Resulting HCV RNA titers were measured using Northern blot or real time PCR. Expression of HCV NS3 and NS5A proteins and viral replication were also assessed.

As hypothesized, the investigators found that in cells with replicating infectious HCV particles, NS5A "recruited" c-Raf to the replicon complex, resulting in the activation of c-Raf. But adding sorafenib to the cell cultures efficiently blocked HCV replication and viral gene expression.

In addition, they noted, sorafenib decreased hyperphosphorylated forms of NS5A in HCV-replicating cells and led to production of additional hypophosphorylated forms. Furthermore, sorafenib caused rapid "dissociation" or destruction of lipid droplets, which play a role in HCV entry into cells.

"We provide evidence that the antiviral effect of sorafenib indeed is caused by inhibition of c-Raf," the study authors wrote. "By contrast, inhibition of targets downstream of c-Raf or inhibition of tyrosine kinases by sunitinib [another cancer chemotherapy] did not affect HCV replication."

"Our data demonstrate that the well-characterized anti-tumor drug sorafenib efficiently blocks HCV replication in vitro," they concluded. "This novel effect of sorafenib should be further explored as an antiviral strategy for patients with chronic HCV infection."

University of Freiburg, Department of Medicine II, Freiburg, Germany; University of Kiel, Institute of Infection Medicine, Molecular Medical Virology, Kiel, Germany; Institut National de la Santé et de la Recherche Médicale, Strasbourg, France; Université Louis Pasteur, Strasbourg, France; TU-Munich, Department of Medicine II, Munich, Germany.


K Himmelsbach, D Sauter, T Baumert, and others. New aspects of an anti-tumor drug: sorafenib efficiently inhibits HCV replication. Gut 58(12): 1644-1653 (Abstract). December 2009.



























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