Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells

Yuko Murakami, Kazuo Sugiyama, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Keisuke Ojiro, Hakusyo Cho, Nobuhito Taniki, Yoshimasa Saito, Toshiaki Teratani, Yuzo Koda, Takahiro Suzuki, Kyoko Saito, Masayoshi Fukasawa, Masanori Ikeda, Nobuyuki Kato, Takanori Kanai, Hidetsugu Saito

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: We 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. Methods: The 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. Results: Brusatol 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. Conclusions: Brusatol 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.

Original languageEnglish
Article number680
JournalBMC Cancer
Volume18
Issue number1
DOIs
Publication statusPublished - 2018 Jun 25

Fingerprint

NF-E2-Related Factor 2
Liver Neoplasms
Hepacivirus
Hepatocytes
Virus Diseases
Virus Replication
brusatol
RNA
Cell Line
Replicon
Proteins

Keywords

  • Anti-HCV
  • Anticancer
  • Brusatol
  • Chemotherapy
  • Hepatitis C virus
  • Hepatocellular carcinoma
  • Nuclear factor E2-related factor 2
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells. / Murakami, Yuko; Sugiyama, Kazuo; Ebinuma, Hirotoshi; Nakamoto, Nobuhiro; Ojiro, Keisuke; Cho, Hakusyo; Taniki, Nobuhito; Saito, Yoshimasa; Teratani, Toshiaki; Koda, Yuzo; Suzuki, Takahiro; Saito, Kyoko; Fukasawa, Masayoshi; Ikeda, Masanori; Kato, Nobuyuki; Kanai, Takanori; Saito, Hidetsugu.

In: BMC Cancer, Vol. 18, No. 1, 680, 25.06.2018.

Research output: Contribution to journalArticle

Murakami, Y, Sugiyama, K, Ebinuma, H, Nakamoto, N, Ojiro, K, Cho, H, Taniki, N, Saito, Y, Teratani, T, Koda, Y, Suzuki, T, Saito, K, Fukasawa, M, Ikeda, M, Kato, N, Kanai, T & Saito, H 2018, 'Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells', BMC Cancer, vol. 18, no. 1, 680. https://doi.org/10.1186/s12885-018-4588-y
Murakami, Yuko ; Sugiyama, Kazuo ; Ebinuma, Hirotoshi ; Nakamoto, Nobuhiro ; Ojiro, Keisuke ; Cho, Hakusyo ; Taniki, Nobuhito ; Saito, Yoshimasa ; Teratani, Toshiaki ; Koda, Yuzo ; Suzuki, Takahiro ; Saito, Kyoko ; Fukasawa, Masayoshi ; Ikeda, Masanori ; Kato, Nobuyuki ; Kanai, Takanori ; Saito, Hidetsugu. / Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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abstract = "Background: We 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. Methods: The 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. Results: Brusatol 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. Conclusions: Brusatol 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.",
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AU - Sugiyama, Kazuo

AU - Ebinuma, Hirotoshi

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AU - Ojiro, Keisuke

AU - Cho, Hakusyo

AU - Taniki, Nobuhito

AU - Saito, Yoshimasa

AU - Teratani, Toshiaki

AU - Koda, Yuzo

AU - Suzuki, Takahiro

AU - Saito, Kyoko

AU - Fukasawa, Masayoshi

AU - Ikeda, Masanori

AU - Kato, Nobuyuki

AU - Kanai, Takanori

AU - Saito, Hidetsugu

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N2 - Background: We 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. Methods: The 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. Results: Brusatol 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. Conclusions: Brusatol 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.

AB - Background: We 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. Methods: The 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. Results: Brusatol 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. Conclusions: Brusatol 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.

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