title: Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress.
abstract: Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Misao
authors.initials: M
authors.lastname: Kuroki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ariumi
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Dansako
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D001152:Arsenicals; D010087:Oxides; D012367:RNA, Viral; D013481:Superoxides; D005978:Glutathione; D000077237:Arsenic Trioxide