Department of Hepatobiliary Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, China.
Department of Hepatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Pharmacol Res Perspect. 2022 Jun;10(3):e00954. doi: 10.1002/prp2.954.
Advanced hepatocellular carcinoma (HCC) results in generally poor clinical outcomes and necessitates better therapeutic strategies. Ivermectin, which is an existing anti-parasitic drug, has been recently identified as a novel anti-cancer drug. In line with previous efforts, this work demonstrates the translational potential of ivermectin to treat advanced HCC. We demonstrated that ivermectin at clinically relevant concentrations was active against growth and survival in multiple HCC cell lines. We showed that ivermectin had the potential to inhibit metastasis and target HCC stem cell functions. Mechanism studies correlated well with cellular phenotypes observed in ivermectin-treated cells, and demonstrated inhibition of mTOR/STAT3 pathway, suppression of epithelial mesenchymal transition (EMT) and reduced expression of stem cell markers. We further demonstrated that ivermectin inhibited tumor formation and growth in HCC xenograft mouse model, without causing significant toxicity in the mice. Using combination index (CI), we showed that ivermectin and sorafenib were synergistic in HCC in vitro, and this was further confirmed in vivo. Our work demonstrates the potent anti-HCC activities of ivermectin and its multiple targets on essential oncogenic pathways. Our findings provide preclinical evidence to initialize clinical trial using ivermectin and sorafenib for treating advanced HCC.
晚期肝细胞癌（HCC）的临床预后通常较差，因此需要更好的治疗策略。伊维菌素是一种现有的抗寄生虫药物，最近被鉴定为一种新型抗癌药物。与之前的研究一致，本研究证明了伊维菌素在治疗晚期 HCC 方面具有转化潜力。我们证明了在临床相关浓度下，伊维菌素可有效抑制多种 HCC 细胞系的生长和存活。我们表明，伊维菌素有可能抑制转移并靶向 HCC 干细胞功能。机制研究与伊维菌素处理细胞中观察到的细胞表型密切相关，并证明了 mTOR/STAT3 通路的抑制、上皮间质转化（EMT）的抑制和干细胞标志物的表达降低。我们进一步证明，伊维菌素在 HCC 异种移植小鼠模型中抑制肿瘤的形成和生长，而不会导致小鼠产生明显的毒性。通过使用组合指数（CI），我们表明伊维菌素和索拉非尼在 HCC 中具有协同作用，这在体内得到了进一步证实。我们的研究结果表明伊维菌素具有强大的抗 HCC 活性，并且针对关键致癌途径的多个靶点。我们的研究结果为使用伊维菌素和索拉非尼治疗晚期 HCC 启动临床试验提供了临床前证据。
