Arsenic trioxide inhibits hepatitis C Virus RNA replication through modulation of the glutathione redox system and oxidative stress

Misao Kuroki, Yasuo Ariumi, Masanori Ikeda, Hiromichi Dansako, Takaji Wakita, Nobuyuki Kato

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 VV-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.

Original languageEnglish
Pages (from-to)2338-2348
Number of pages11
JournalJournal of Virology
Volume83
Issue number5
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Hepatitis C virus
Virus Replication
arsenic
Hepacivirus
Oxidation-Reduction
Glutathione
glutathione
Oxidative Stress
oxidative stress
RNA
Superoxides
arsenic trioxide
RNA replication
Genotype
acetylcysteine
Acute Promyelocytic Leukemia
genotype
Virus Diseases
Human immunodeficiency virus 1
leukemia

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Arsenic trioxide inhibits hepatitis C Virus RNA replication through modulation of the glutathione redox system and oxidative stress. / Kuroki, Misao; Ariumi, Yasuo; Ikeda, Masanori; Dansako, Hiromichi; Wakita, Takaji; Kato, Nobuyuki.

In: Journal of Virology, Vol. 83, No. 5, 03.2009, p. 2338-2348.

Research output: Contribution to journalArticle

@article{3ff8fec82f484cbd95ce4a7b31218bc2,
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 VV-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.",
author = "Misao Kuroki and Yasuo Ariumi and Masanori Ikeda and Hiromichi Dansako and Takaji Wakita and Nobuyuki Kato",
year = "2009",
month = "3",
doi = "10.1128/JVI.01840-08",
language = "English",
volume = "83",
pages = "2338--2348",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Arsenic trioxide inhibits hepatitis C Virus RNA replication through modulation of the glutathione redox system and oxidative stress

AU - Kuroki, Misao

AU - Ariumi, Yasuo

AU - Ikeda, Masanori

AU - Dansako, Hiromichi

AU - Wakita, Takaji

AU - Kato, Nobuyuki

PY - 2009/3

Y1 - 2009/3

N2 - 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 VV-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.

AB - 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 VV-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.

UR - http://www.scopus.com/inward/record.url?scp=60049097867&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60049097867&partnerID=8YFLogxK

U2 - 10.1128/JVI.01840-08

DO - 10.1128/JVI.01840-08

M3 - Article

VL - 83

SP - 2338

EP - 2348

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 5

ER -