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


RESULTS
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.
Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Shigeyuki
S
Takeshita
Tatsuki
T
Ichikawa
Naota
N
Taura
Hisamitsu
H
Miyaaki
Toshihisa
T
Matsuzaki
Masashi
M
Otani
Toru
T
Muraoka
Motohisa
M
Akiyama
Satoshi
S
Miuma
Eisuke
E
Ozawa
Masanori
M
Ikeda
Nobuyuki
N
Kato
Hajime
H
Isomoto
Fuminao
F
Takeshima
Kazuhiko
K
Nakao
D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000276:immunology; D012093:Replicon; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000897:Anti-Ulcer Agents; D004224:Diterpenes; D050832:Interferon-Stimulated Gene Factor 3; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; C031049:geranylgeranylacetone