Abstract
BackgroundWe previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored.MethodsThe anti-HCV effect of brusatol was investigated by analyzing HCV RNA and proteins in a hepatic cell line persistently-infected with HCV, HPI cells, and by analyzing HCV replication in a replicon-replicating hepatic cell line, OR6 cells. Then, dual anti-HCV and anticancer effects of brusatol and enhancement of the effects by the combination of brusatol with anticancer drugs including sorafenib, which has been reported to have the dual effects, were then investigated.ResultsBrusatol suppressed the persistent HCV infection at both the RNA and protein levels in association with a reduction in Nrf2 protein in the HPI cells. Analysis of the OR6 cells treated with brusatol indicated that brusatol inhibited HCV persistence by inhibiting HCV replication. Combination of brusatol with an anticancer drug not only enhanced the anticancer effect but also, in the case of the combination with sorafenib, strongly suppressed HCV infection.ConclusionsBrusatol has dual anti-HCV and anticancer effects and can enhance the comparable effects of sorafenib. There is therefore the potential for combination therapy of brusatol and sorafenib for HCV-related hepatocellular carcinoma.
Highlights
We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection
P-Nrf2 was expressed exclusively in the nuclei of 45% (9/20) of the HCV-positive hepatocellular carcinoma (HCC) (C-HCC) specimens on the array examined, whereas only 5% (1/20) of the non-HCC specimens without either HCV or HBV infection were positive for phosphorylated Nrf2 (p-Nrf2)
As shown in the immunofluorescence analysis (Fig. 1b), p-Nrf2 was expressed exclusively in the nuclei of the HPI cells, in which HCV core protein was positively stained in cytosol. p-Nrf2 was exclusively expressed in the nuclei of the HCV-negative hepatoma cell lines, relatively few of the HepG2 cells were p-Nrf2-positive
Summary
We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. Chronic infection with hepatitis C virus (HCV) has been a worldwide health problem for decades, frequently leading to serious liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC) [1, 2]. An interferon-based regimen has been the major therapy for HCV despite various adverse effects. Several kinds of direct-acting antivirals (DAAs), which target proteins of the replication complex of HCV, including the nonstructural protein (NS), NS5A, and NS5B, have been developed, and combination regimens of such DAAs have achieved a sustained viral response more than 90% of the patients without using interferons [3].
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