multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2011-03, Vol.68 (6), p.1079-1090
Main Authors: Michaelis, Martin, Paulus, Christina, Löschmann, Nadine, Dauth, Stephanie, Stange, Elisabeth, Doerr, Hans Wilhelm, Nevels, Michael, Cinatl, Jindrich Jr
Format: Article
Language:English
Subjects:
Antigens
Antiviral drugs
Antiviral therapy
Benzenesulfonates - pharmacology
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer chemotherapy
Cell Biology
Chemotherapy
Cytomegalovirus - drug effects
DNA Primers - genetics
Genes, Immediate-Early - genetics
Human cytomegalovirus
Human herpesvirus 5
Humans
Immediate early antigen
Immunoblotting
Kinase inhibitor
Kinases
Life Sciences
Luciferases
Niacinamide - analogs & derivatives
Oncomodulation
Pathology
Phenylurea Compounds
Promoter Regions, Genetic - genetics
Protein Kinase Inhibitors - pharmacology
Pyridines - pharmacology
Raf
raf Kinases - antagonists & inhibitors
Research Article
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Sorafenib
Virology
Virus Replication - drug effects
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Summary:Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-010-0510-8