Sulforaphane Suppresses Hepatitis C Virus Replication by Up-Regulating Heme Oxygenase-1 Expression through PI3K/Nrf2 Pathway

• Published in: PloS one Vol. 11; no. 3; p. e0152236
• Main Authors: Yu, Jung-Sheng, Chen, Wei-Chun, Tseng, Chin-Kai, Lin, Chun-Kuang, Hsu, Yao-Chin, Chen, Yen-Hsu, Lee, Jin-Ching
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.03.2016; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Antibiotics; Antioxidants; Antiviral agents; Antiviral Agents - pharmacology; Antiviral drugs; Bilirubin - biosynthesis; Biliverdine - biosynthesis; Biology and Life Sciences; Cell Line, Tumor; Complications and side effects; Dosage and administration; Drug Synergism; Drug therapy; Drugs; Enzymes; FDA approval; Gene expression; Genetic aspects; Genotype & phenotype; Health aspects; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - metabolism; Hepacivirus - drug effects; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatology; Humans; Infections; Infectious diseases; Interferon; Interferons - pharmacology; Isothiocyanates - pharmacology; Liver; Liver diseases; Medical research; Medicine; Medicine and Health Sciences; Models, Biological; Natural products; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxygenase; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physiological aspects; Replication; Replicon - drug effects; Research and analysis methods; Ribonucleic acid; Risk factors; RNA; RNA, Viral - metabolism; Rodents; Science; Signaling; Sulforaphane; Synergistic effect; Transcriptional Activation - drug effects; Tumorigenesis; Up-Regulation - drug effects; Vegetables; Viral infections; Viral Nonstructural Proteins - metabolism; Virus replication; Virus Replication - drug effects; Viruses; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152236

Hepatitis C virus (HCV) infection-induced oxidative stress is a major risk factor for the development of HCV-associated liver disease. Sulforaphane (SFN) is an antioxidant phytocompound that acts against cellular oxidative stress and tumorigenesis. However, there is little known about its anti-viral activity. In this study, we demonstrated that SFN significantly suppressed HCV protein and RNA levels in HCV replicon cells and infectious system, with an IC50 value of 5.7 ± 0.2 μM. Moreover, combination of SFN with anti-viral drugs displayed synergistic effects in the suppression of HCV replication. In addition, we found nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 induction in response to SFN and determined the signaling pathways involved in this process, including inhibition of NS3 protease activity and induction of IFN response. In contrast, the anti-viral activities were attenuated by knockdown of HO-1 with specific inhibitor (SnPP) and shRNA, suggesting that anti-HCV activity of SFN is dependent on HO-1 expression. Otherwise, SFN stimulated the phosphorylation of phosphoinositide 3-kinase (PI3K) leading Nrf2-mediated HO-1 expression against HCV replication. Overall, our results indicated that HO-1 is essential in SFN-mediated anti-HCV activity and provide new insights in the molecular mechanism of SFN in HCV replication.