Nrf2 抑制剂抑制丙型肝炎病毒和肝癌细胞的双重作用。
Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells.
机构信息
Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 105-8512, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan.
出版信息
BMC Cancer. 2018 Jun 25;18(1):680. doi: 10.1186/s12885-018-4588-y.
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.
背景
我们之前的研究表明，核因子 E2 相关因子 2（Nrf2）的敲低导致丙型肝炎病毒（HCV）感染受到抑制。在这项研究中，我们探讨了 Nrf2 抑制剂溴夫定是否具有双重抗 HCV 和抗癌作用。
方法
通过分析持续感染 HCV 的肝细胞系 HPI 细胞中的 HCV RNA 和蛋白，以及分析复制子复制的肝细胞系 OR6 细胞中的 HCV 复制，研究溴夫定的抗 HCV 作用。然后，研究了溴夫定的双重抗 HCV 和抗癌作用，以及溴夫定与包括索拉非尼在内的抗癌药物联合使用的增效作用，索拉非尼已被报道具有双重作用。
结果
溴夫定降低了 HPI 细胞中的 Nrf2 蛋白水平，从而抑制了持续的 HCV 感染，同时降低了 HCV 的 RNA 和蛋白水平。对用溴夫定处理的 OR6 细胞的分析表明，溴夫定通过抑制 HCV 复制抑制了 HCV 的持续感染。溴夫定与抗癌药物联合使用不仅增强了抗癌作用，而且在与索拉非尼联合使用时，强烈抑制了 HCV 感染。
结论
溴夫定具有双重抗 HCV 和抗癌作用，并能增强索拉非尼的类似作用。因此，溴夫定和索拉非尼联合治疗 HCV 相关肝细胞癌具有潜在的应用前景。
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