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 language | English |
|---|---|
| Pages (from-to) | 195-202 |
| Number of pages | 8 |
| Journal | Journal of Gastroenterology |
| Volume | 47 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2012 |
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Keywords
- GGA
- HCV
- Interferon
- MTOR
- STAT-1
ASJC Scopus subject areas
- Gastroenterology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells
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
PY - 2012/2
Y1 - 2012/2
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.
AB - 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.
KW - GGA
KW - HCV
KW - Interferon
KW - MTOR
KW - STAT-1
UR - http://www.scopus.com/inward/record.url?scp=84862334283&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862334283&partnerID=8YFLogxK
U2 - 10.1007/s00535-011-0481-z
DO - 10.1007/s00535-011-0481-z
M3 - Article
C2 - 22038554
AN - SCOPUS:84862334283
VL - 47
SP - 195
EP - 202
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
SN - 0944-1174
IS - 2
ER -