Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
J Gastroenterol. 2012 Feb;47(2):195-202. doi: 10.1007/s00535-011-0481-z. Epub 2011 Oct 25.
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.
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.
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.
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.
香叶基丙酮（GGA）是一种类异戊二烯化合物，包括视黄醇，在日本已被口服用于治疗溃疡。GGA 通过刺激人肝癌细胞中 ISGF3 的形成，作为一种有效的抗病毒基因表达诱导剂。该药物副作用少，与聚乙二醇干扰素和利巴韦林联合使用时可增强 IFN 的作用。本研究在复制子系统中验证了 GGA 对 HCV 的抗活性。此外，还在复制子细胞中研究了其抗 HCV 活性的机制。
使用稳定携带全长基因型 1 复制子的 OR6 细胞，该复制子含有 Renilla 荧光素酶基因 ORN/C-5B/KE，以检测 GGA 对 HCV 抑制作用的影响。处理后，用 Renilla 裂解试剂收获细胞，然后按照制造商的方案进行荧光素酶测定。
结果表明 GGA 具有抗 HCV 活性。GGA 以时间和剂量依赖的方式诱导抗 HCV 复制子活性。GGA 不会激活 STAT-1 上的酪氨酸 701 和丝氨酸 727，也不会诱导 OR6 细胞中的 HSP-70。抗 HCV 作用取决于 GGA 诱导的 mTOR 活性，而不是 STAT-1 活性和 PKR。IFN 与 GGA 联合使用具有相加作用。
GGA 具有 mTOR 依赖性抗 HCV 活性。GGA 的抗 HCV 活性可能与 IFN 互补。将来有必要检查 GGA 和 IFN 联合用于 HCV 患者的临床疗效。
