Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells

Shigeyuki Takeshita, Tatsuki Ichikawa, Naota Taura, Hisamitsu Miyaaki, Toshihisa Matsuzaki, Masashi Otani, Toru Muraoka, Motohisa Akiyama, Satoshi Miuma, Eisuke Ozawa, Masanori Ikeda, Nobuyuki Kato, Hajime Isomoto, Fuminao Takeshima, Kazuhiko Nakao

Research output: Contribution to journalArticle

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Abstract

Background Geranylgeranylacetone (GGA), an isoprenoid compound which includes retinoids, has been used orally as an anti-ulcer drug in Japan. GGA acts as a potent inducer of anti-viral gene expression by stimulating ISGF3 formation in human hepatoma cells. This drug has few side effects and reinforces the effect of IFN when administered in combination with peg-IFN and ribavirin. This study verified the anti-HCV activity of GGA in a replicon system. In addition, mechanisms of anti-HCV activity were examined in the replicon cells. Methods OR6 cells stably harboring the full-length genotype 1 replicon containing the Renilla luciferase gene, ORN/C-5B/KE, were used to examine the influence of the anti-HCV effect of GGA. After treatment, the cells were harvested with Renilla lysis reagent and then subjected to a luciferase assay according to the manufacturer's protocol. Result The results showed that GGA had anti-HCV activity. GGA induced anti-HCV replicon activity in a time- and dose-dependent manner. GGA did not activate the tyrosine 701 and serine 727 on STAT-1, and did not induce HSP-70 in OR6 cells. The anti-HCV effect depended on the GGA induced mTOR activity, not STAT-1 activity and PKR. An additive effect was observed with a combination of IFN and GGA. Conclusions GGA has mTOR dependent anti-HCV activity. There is a possibility that the GGA anti-HCV activity can be complimented by IFN. It will be necessary to examine the clinical effectiveness of the combination of GGA and IFN for HCV patients in the future.

Original languageEnglish
Pages (from-to)195-202
Number of pages8
JournalJournal of Gastroenterology
Volume47
Issue number2
DOIs
Publication statusPublished - Feb 2012

Fingerprint

geranylgeranylacetone
Hepacivirus
Hepatocellular Carcinoma
Replicon
Renilla
Renilla Luciferases
Anti-Ulcer Agents

Keywords

  • GGA
  • HCV
  • Interferon
  • MTOR
  • STAT-1

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Takeshita, S., Ichikawa, T., Taura, N., Miyaaki, H., Matsuzaki, T., Otani, M., ... Nakao, K. (2012). Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells. Journal of Gastroenterology, 47(2), 195-202. https://doi.org/10.1007/s00535-011-0481-z

Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells. / Takeshita, Shigeyuki; Ichikawa, Tatsuki; Taura, Naota; Miyaaki, Hisamitsu; Matsuzaki, Toshihisa; Otani, Masashi; Muraoka, Toru; Akiyama, Motohisa; Miuma, Satoshi; Ozawa, Eisuke; Ikeda, Masanori; Kato, Nobuyuki; Isomoto, Hajime; Takeshima, Fuminao; Nakao, Kazuhiko.

In: Journal of Gastroenterology, Vol. 47, No. 2, 02.2012, p. 195-202.

Research output: Contribution to journalArticle

Takeshita, S, Ichikawa, T, Taura, N, Miyaaki, H, Matsuzaki, T, Otani, M, Muraoka, T, Akiyama, M, Miuma, S, Ozawa, E, Ikeda, M, Kato, N, Isomoto, H, Takeshima, F & Nakao, K 2012, 'Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells', Journal of Gastroenterology, vol. 47, no. 2, pp. 195-202. https://doi.org/10.1007/s00535-011-0481-z
Takeshita, Shigeyuki ; Ichikawa, Tatsuki ; Taura, Naota ; Miyaaki, Hisamitsu ; Matsuzaki, Toshihisa ; Otani, Masashi ; Muraoka, Toru ; Akiyama, Motohisa ; Miuma, Satoshi ; Ozawa, Eisuke ; Ikeda, Masanori ; Kato, Nobuyuki ; Isomoto, Hajime ; Takeshima, Fuminao ; Nakao, Kazuhiko. / Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells. In: Journal of Gastroenterology. 2012 ; Vol. 47, No. 2. pp. 195-202.
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abstract = "Background Geranylgeranylacetone (GGA), an isoprenoid compound which includes retinoids, has been used orally as an anti-ulcer drug in Japan. GGA acts as a potent inducer of anti-viral gene expression by stimulating ISGF3 formation in human hepatoma cells. This drug has few side effects and reinforces the effect of IFN when administered in combination with peg-IFN and ribavirin. This study verified the anti-HCV activity of GGA in a replicon system. In addition, mechanisms of anti-HCV activity were examined in the replicon cells. Methods OR6 cells stably harboring the full-length genotype 1 replicon containing the Renilla luciferase gene, ORN/C-5B/KE, were used to examine the influence of the anti-HCV effect of GGA. After treatment, the cells were harvested with Renilla lysis reagent and then subjected to a luciferase assay according to the manufacturer's protocol. Result The results showed that GGA had anti-HCV activity. GGA induced anti-HCV replicon activity in a time- and dose-dependent manner. GGA did not activate the tyrosine 701 and serine 727 on STAT-1, and did not induce HSP-70 in OR6 cells. The anti-HCV effect depended on the GGA induced mTOR activity, not STAT-1 activity and PKR. An additive effect was observed with a combination of IFN and GGA. Conclusions GGA has mTOR dependent anti-HCV activity. There is a possibility that the GGA anti-HCV activity can be complimented by IFN. It will be necessary to examine the clinical effectiveness of the combination of GGA and IFN for HCV patients in the future.",
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AU - Takeshita, Shigeyuki

AU - Ichikawa, Tatsuki

AU - Taura, Naota

AU - Miyaaki, Hisamitsu

AU - Matsuzaki, Toshihisa

AU - Otani, Masashi

AU - Muraoka, Toru

AU - Akiyama, Motohisa

AU - Miuma, Satoshi

AU - Ozawa, Eisuke

AU - Ikeda, Masanori

AU - Kato, Nobuyuki

AU - Isomoto, Hajime

AU - Takeshima, Fuminao

AU - Nakao, Kazuhiko

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N2 - Background Geranylgeranylacetone (GGA), an isoprenoid compound which includes retinoids, has been used orally as an anti-ulcer drug in Japan. GGA acts as a potent inducer of anti-viral gene expression by stimulating ISGF3 formation in human hepatoma cells. This drug has few side effects and reinforces the effect of IFN when administered in combination with peg-IFN and ribavirin. This study verified the anti-HCV activity of GGA in a replicon system. In addition, mechanisms of anti-HCV activity were examined in the replicon cells. Methods OR6 cells stably harboring the full-length genotype 1 replicon containing the Renilla luciferase gene, ORN/C-5B/KE, were used to examine the influence of the anti-HCV effect of GGA. After treatment, the cells were harvested with Renilla lysis reagent and then subjected to a luciferase assay according to the manufacturer's protocol. Result The results showed that GGA had anti-HCV activity. GGA induced anti-HCV replicon activity in a time- and dose-dependent manner. GGA did not activate the tyrosine 701 and serine 727 on STAT-1, and did not induce HSP-70 in OR6 cells. The anti-HCV effect depended on the GGA induced mTOR activity, not STAT-1 activity and PKR. An additive effect was observed with a combination of IFN and GGA. Conclusions GGA has mTOR dependent anti-HCV activity. There is a possibility that the GGA anti-HCV activity can be complimented by IFN. It will be necessary to examine the clinical effectiveness of the combination of GGA and IFN for HCV patients in the future.

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KW - STAT-1

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