Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells
| Autor: | Dirk Daelemans, Els Scheers, Johan Neyts, Els Vanstreels, Leen Delang, Ben Verpaalen, Catherine M. Verfaillie, Mareike Grabner, Nicky Helsen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Statin
Indoles Pyrrolidines medicine.drug_class Hepatitis C virus Hepacivirus medicine.disease_cause Virus Replication Biochemistry Antiviral Agents Flow cytometry Fatty Acids Monounsaturated Viral Proteins Cell Line Tumor Drug Resistance Viral medicine Humans Replicon ATP Binding Cassette Transporter Subfamily B Member 1 Fluvastatin Pharmacology biology medicine.diagnostic_test Anticholesteremic Agents Imidazoles Valine Virology Molecular biology In vitro Enzyme Activation Gene Expression Regulation Hydroxymethylglutaryl-CoA-Reductases NADP-dependent HMG-CoA reductase Host-Pathogen Interactions biology.protein Hepatocytes Efflux Carbamates Oligopeptides medicine.drug Signal Transduction |
| Zdroj: | Biochemical pharmacology. 96(3) |
| ISSN: | 1873-2968 |
| Popis: | A number of statins, the cholesterol-lowering drugs, inhibit the in vitro replication of hepatitis C virus (HCV). In HCV-infected patients, addition of statins to the earlier standard of care therapy (pegIFN-α and ribavirin) resulted in increased sustained virological response rates. The mechanism by which statins inhibit HCV replication has not yet been elucidated. In an attempt to gain insight in the underlying mechanism, hepatoma cells carrying an HCV replicon were passaged in the presence of increasing concentrations of fluvastatin. Fluvastatin-resistant replicon containing cells could be generated and proved ∼8-fold less susceptible to fluvastatin than wild-type cultures. The growth efficiency of the resistant replicon containing cells was comparable to that of wild-type replicon cells. The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes. The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by qRT-PCR and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM. In conclusion, we demonstrate that statin resistance in HCV replicon containing hepatoma cells is conferred by changes in the cellular environment. publisher: Elsevier articletitle: Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells journaltitle: Biochemical Pharmacology articlelink: http://dx.doi.org/10.1016/j.bcp.2015.06.003 content_type: article copyright: Copyright © 2015 Elsevier Inc. All rights reserved. ispartof: Biochemical Pharmacology vol:96 issue:3 pages:190-201 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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