瑞戈非尼已获得美国食品和药物管理局 (FDA) 批准用于治疗肝细胞癌 (HCC) 患者，索拉非尼治疗显示出进展。然而，瑞戈非尼不可避免地存在较高的耐药率，这降低了其临床治疗的有效性。因此，迫切需要找到解决瑞戈非尼耐药问题的潜在方法。双硫仑与铜络合的代谢物二乙基二硫代氨基甲酸酯-铜络合物（CuET）已被发现是一种有效的抗癌候选药物。在本研究中，我们旨在评估CuET对HCC瑞戈非尼耐药的影响并揭示相关机制。通过应用递增的浓度梯度构建瑞戈非尼耐药HCC菌株。本研究采用了一系列全面的方法，包括细胞计数试剂盒-8 (CCK-8) 测定、集落形成测定、细胞周期分析、伤口愈合测定、Transwell 测定、肿瘤异种移植模型和免疫组织化学分析。这些方法用于研究CuET的抗肿瘤活性，评估瑞戈非尼和CuET的联合作用，并阐明CuET介导的瑞戈非尼耐药的分子机制。瑞戈非尼对细胞存活、增殖和迁移的抑制作用降低。与亲代细胞相比，耐药 MHCC-97H (MHCC-97H/REGO) 细胞。 CuET 对各种 HCC 细胞系的细胞存活、增殖和迁移具有显着的抑制作用。 CuET 在体外和体内恢复了 MHCC-97H/REGO HCC 细胞对瑞格非尼的敏感性。从机制上讲，CuET 通过抑制 ERK 信号通路来抑制上皮间质转化 (EMT)，从而逆转 HCC 瑞戈非尼耐药。综上所述，本研究结果表明，CuET 抑制 ERK 信号通路的激活，从而抑制上皮间质转化（EMT），并随后在体内和体外逆转 HCC 中的瑞戈非尼耐药性。这项研究为改善瑞格非尼耐药性 HCC 的治疗提供了新的思路和潜在策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism.Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance.The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway.Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.