Abstract：
Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial-mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (GLUT1, HK2, LDHA, and PEPCK), stemness (OCT4), and drug resistance (ABCG2) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC.
摘要：
索拉非尼是第一个批准的用于晚期肝癌的全身靶向药物;然而，当单独使用时，耐药性会导致疗效大大降低。这里,我们证明了氯硝柳胺，一种由美国食品和药物管理局批准的抗蠕虫剂，可用于提高索拉非尼耐药肝癌细胞对索拉非尼的敏感性。我们产生了索拉非尼抗性HCC细胞系（HepG2215_R和Hep3B_R），其IGF-1R水平升高，并且在干性和上皮-间质转化方面具有很强的特性。发现氯硝柳胺可有效提高细胞系及其类器官中的索拉非尼敏感性。潜在的机制涉及癌症干性的调节，IGF-1R/p-IGF1R/OCT4和代谢变化。索拉非尼和氯硝柳胺的组合，但不是linsitinib,有效抑制IGF-1R/OCT4的表达，产生了协同组合指数(CI)，和减弱的干性相关特性，如继发性肿瘤球形成和细胞迁移在索拉非尼耐药肝癌细胞。值得注意的是,氯硝柳胺可显着抑制索拉非尼诱导的IGF-1R磷酸化。氯硝柳胺有效下调索拉非尼诱导的与糖酵解相关的基因表达(GLUT1、HK2、LDHA、和PEPCK），干性(OCT4)，和耐药性（ABCG2），并增强索拉非尼在体外降低线粒体膜电位的能力。氯硝柳胺和索拉非尼的组合在体内的协同作用进一步通过由凋亡调节导致的肿瘤大小和肿瘤体积的减小来证明。我们的结果表明，氯硝柳胺可以通过IGF-1R/干性调节和代谢变化增强索拉非尼耐药HCC细胞的索拉非尼敏感性。我们的研究结果强调了提高肝癌患者索拉非尼敏感性的实用临床策略。
