title: Curcumin inhibits HCV replication by induction of heme oxygenase-1 and             suppression of AKT.
abstract: Although hepatitis C virus (HCV) affects approximately 130-170 million people worldwide, no vaccines are available. HCV is an important cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, leading to the need for liver transplantation. In this study, curcumin, a constituent used in traditional Chinese medicine, has been evaluated for its anti-HCV activity and mechanism, using a human hepatoma cell line containing the HCV genotype 1b subgenomic replicon. Below the concentration of 20% cytotoxicity, curcumin dose-dependently inhibited HCV replication by luciferase reporter gene assay, HCV RNA detection and HCV protein analysis. Under the same conditions, curcumin also dose-dependently induced heme oxygenase-1 with the highest induction at 24 h. Hemin, a heme oxygenase-1 inducer, also inhibited HCV protein expression in a dose-dependent manner. The knockdown of heme oxygenase-1 partially reversed the curcumin-inhibited HCV protein expression. In addition to the heme oxygenase-1 induction, signaling molecule activities of AKT, extracellular signal-regulated kinases (ERK) and nuclear factor-κB (NF-κB) were inhibited by curcumin. Using specific inhibitors of PI3K-AKT, MEK-ERK and NF-κB, the results suggested that only PI3K-AKT inhibition is positively involved in curcumin-inhibited HCV replication. Inhibition of ERK and NF-κB was likely to promote HCV protein expression. In summary, curcumin inhibited HCV replication by heme oxygenase-1 induction and AKT pathway inhibition. Although curcumin also inhibits ERK and NF-κB activities, it slightly increased the HCV protein expression. This result may provide information when curcumin is used as an adjuvant in anti-HCV therapy.
authors.affiliation: Department of Chinese Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan, ROC.
authors.forename: Ming-Ho
authors.initials: MH
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lee
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Chuang
authors.forename: Yi-Zhen
authors.initials: YZ
authors.lastname: Li
authors.forename: Sin-Tzu
authors.initials: ST
authors.lastname: Ning
authors.forename: Jung-Chou
authors.initials: JC
authors.lastname: Chen
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liu
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology / Q000502:physiology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003474:Curcumin; D051547:Heme Oxygenase-1; D006427:Hemin; D051057:Proto-Oncogene Proteins c-akt; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase