Scientists have identified two proteins found on the surface of liver cells that help the hepatitis C virus (HCV) enter the cells, the first step in a viral infection that causes liver disease and increases the risk of liver cancer. Both proteins are a type of molecule called receptor tyrosine kinases. Anticancer drugs called tyrosine kinase inhibitors (TKIs) blocked the action of the identified proteins and reduced HCV infection in laboratory models of the disease, reported researchers led by Drs. Joachim Lupberger and Mirjam B. Zeisel from the University of Strasbourg in France. The results were published online April 24 in Nature Medicine.
To identify liver cell proteins that the virus exploits to gain entry, the researchers first used small inhibitory RNAs to block several kinase proteins one by one. They found that silencing the expression of two such proteins—epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2)—stopped HCV particles from entering the cells.
Two approved TKIs, erlotinib and dasatinib, inhibit EGFR and EphA2, respectively. When the researchers treated liver cells with the drugs, HCV entry was impaired. Two other TKIs that inhibit EGFR, gefitinib and lapatinib, had similar effects. In experiments testing cell-to-cell transmission of HCV, erlotinib and dasatinib stopped the virus from spreading from infected cells for up to 2 weeks (the length of the experiment).
Further studies of the cell-signaling networks controlled by EGFR and EphA2 indicated that these proteins do not appear to be necessary for HCV to bind to cells. Instead, they seem to be involved in the virus’ ability to enter the cell. When tested in a mouse model of HCV infection, erlotinib substantially reduced the level of viral infection and was well tolerated.
Chronic hepatitis infection is one of the most common causes of liver cancer, and current treatments are inadequate. Although these findings are preliminary, the authors suggest that targeting receptor tyrosine kinases may provide a new way to prevent HCV infection after exposure and to treat existing HCV infections.
NCI Cancer Bulletin for May 3, 2011 - National Cancer Institute
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