PDF(Pubmed)
Abstract：
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypIs) represent such new drugs. We demonstrate that the nonimmunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we show that the HCV infection of humanized mice results in the progressive development of HCC. This is true for the four genotypes tested (1 to 4). Remarkably, we demonstrate that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks after infection when HCC is well established. Importantly, we show that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC, while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
摘要：
迫切需要鉴定抑制HCV诱导的肝细胞癌（HCC）的新药。我们的工作表明，亲环蛋白抑制剂（CypIs）代表了这种新药。我们证明，非免疫抑制性环孢素A（CsA）类似物（CsAa）rencofilstat具有双重治疗HCV感染和HCV诱导的HCC的治疗活性。具体来说,我们表明，人源化小鼠的HCV感染导致肝癌的进行性发展。这对于测试的四种基因型(1至4)是正确的。值得注意的是,我们证明rencofilstat抑制HCV诱导的HCC在小鼠中的发展，即使在感染后16周添加时，HCC已经确立。重要的是,我们显示rencofilstat显著降低HCC进展,而与抗HCV活性无关.的确,CypIrencofilstat抑制HCC，而其他抗HCV药物如NS5A（NS5Ai）和NS5B（NS5Bi）不能降低HCC。总之,这项研究首次表明，CypIrencofilstat是治疗HCV诱导的HCC的有效治疗剂。
