Liver
Cancer Drug Sorafenib (Nexavar) Inhibits Hepatitis
C Virus Replication in Laboratory Study
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.
1/08/10
Reference
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.
