Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Hwang, Der Ren; Tsai, Yuan Chin; Lee, Jin‐Ching; Huang, Kuo Kuei; Lin, Ren Kuo; Ho, Chia Hua; Chiou, Jeng‐Min; Lin, Ying Ting; Hsu, John; Yeh, Chau Ting

doi:10.1128/aac.48.8.2876-2882.2004

Cited by 39 publications

(28 citation statements)

References 39 publications

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“…However, As had no detectable effects on viral expression post-integration or virion assembly. On the other hand, As has been shown to be a potent inhibitor of Hepatitis C virus replication, possibly by interfering with cellular factors necessary for replication (Hwang et al, 2004). A similar result was obtained for HSV, where As increased the stability of the replication protein compartments that need to be disrupted for successful replication and production of progeny virus (Burkham et al, 2001).…”

Section: Effects Of Xenobiotics On Host Resistancesupporting

confidence: 63%

“…This finding was interpreted to mean that As in food had enhanced the pathogenicity of the virus (Pass et al, 1979). However, As has been shown to increase the stability of the replication protein compartments that need to be disrupted for successful replication and production of progeny HSV (Burkham et al, 2001) and to be a potent inhibitor of hepatitis C virus replication (Hwang et al, 2004). Data also show that Ca causes conformation changes in rotaviruses (Pando et al, 2002), Mn causes changes in virulence of HIV (Vartanian et al, 1999), and Cd reactivates latent HSV (Fawl et al, 1996).…”

Section: Discussionmentioning

confidence: 63%

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Interactions between Infections, Nutrients and Xenobiotics

2005

TemaNord

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Section: Effects Of Xenobiotics On Host Resistancesupporting

confidence: 63%

Section: Discussionmentioning

confidence: 63%

Interactions between Infections, Nutrients and Xenobiotics

2005

TemaNord

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“…Indeed, ATO has been shown to increase retroviral infectivity, such as human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus infectivity, but the mechanisms of this change are not well understood (5,6,32,44,47,50,57). In contrast, ATO was recently reported to inhibit the replication of HCV subgenomic replicon RNA (24). However, it also remains unclear how ATO inhibits the HCV RNA replication.…”

mentioning

confidence: 96%

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Kuroki

Ariumi

Ikeda

et al. 2009

J Virol

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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.Hepatitis C virus (HCV) is the causative agent of chronic hepatitis, which progresses to liver cirrhosis and hepatocellular carcinoma. HCV is an enveloped virus with a positive singlestranded 9.6-kb RNA genome, which encodes a large polyprotein precursor of approximately 3,000 amino acid residues. This polyprotein is cleaved by a combination of the host and viral proteases into at least 10 proteins in the following order: core, envelope 1 (E1), E2, p7, nonstructural 2 (NS2), NS3, NS4A, NS4B, NS5A, and NS5B (30).Alpha interferon has been used as an effective anti-HCV reagent in clinical therapy for patients with chronic hepatitis C. The current combination treatment with pegylated alpha interferon and ribavirin, a nucleoside analogue, has been shown to improve the sustained virological response rate to more than 50% (15). However, the adverse effects of the combination therapy and the limited efficacy against genotype 1b warrant the development of new anti-HCV reagents.Arsenic trioxide (ATO) (As 2 O 3 , arsenite) has been used as a therapeutic reagent in acute promyelocytic leukemia, which bears an oncogenic PML-retinoic acid receptor alpha fusion protein resulting from chromosomal translocation (51,52,68,70). The ATO treatment induces complete remission through degradation of the aberrant PML-retinoic acid receptor ␣ (70). The PML tumor suppressor protein is required for formation of the PML nuclear body (PML-NB), also known as nuclear dot 10 or the PML oncogenic domain, which is often disrupted by i...

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“…5A indicate the possibility of a synergistic effect of the combination of IFN-␣ and FLV, we examined whether the effect of this combination is synergistic or additive effect using an isobologram method. 23,24 The anti-HCV activities of IFN-␣ and FLV in combination were evaluated by the OR6 reporter assay. Dose-response inhibition of HCV RNA replication was evaluated for varying IFN-␣ concentrations (0-8 IU/mL) in the presence of various doses of FLV (0-7.5 mol/L).…”

Section: Inhibition Of Hcv Rna Replication By Statinsmentioning

confidence: 99%

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

et al. 2006

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We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A ( P ersistent hepatitis C virus (HCV) infection causes liver fibrosis and hepatocellular carcinoma. Approximately 170 million people worldwide are infected with HCV. The combination of pegylated interferon (IFN) with ribavirin is the current standard therapy for chronic hepatitis C (CHC) and yields a sustained virological response (SVR) rate of about 55%. 1 This means that about 45% of patients with CH C are still threatened by the progression of the disease to cirrhosis and hepatocellular carcinoma. Until 1999, when Lohmann et al. developed the subgenomic replicon of HCV, it was difficult to screen anti-HCV reagents. 2 Many improvements followed that breakthrough, such as a genome-length HCV RNA replication system 3,4 and a subgenomic replicon with a reporter assay system 5 ; more recently, Wakita et al. used a genotype 2a strain, JFH1, to produce the infectious virus in cell culture. [6][7][8] Genotype 1 is the major genotype of HCV found in Japan, the United States, and many other countries. Unfortunately, the SVR rate after combination therapy of pegylated IFN with ribavirin is less than 50% for this genotype. To find a more effective therapy especially for CHC patients with genotype 1, we recently developed a genome-length HCV RNA (strain O of genotype 1b) replication reporter system (OR6), which has been an effective screening tool. 9,10 Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are in wide use for the treatment of hypercholesterolemia. Recently, it

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Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Cited by 39 publications

References 39 publications

Interactions between Infections, Nutrients and Xenobiotics

Interactions between Infections, Nutrients and Xenobiotics

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Different anti-HCV profiles of statins and their potential for combination therapy with interferon

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