Xie Jingyi, Liu Juan, Zhao Man, Li Xinru, Wang Yubo, Zhao Yuelei, Cao Hongxin, Ji Meiju, Chen Mingwei, Hou Peng
Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Int J Mol Sci. 2023 Feb 8;24(4):3418. doi: 10.3390/ijms24043418.
, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Vemurafenib (PLX4032), a specific inhibitor of kinase, exhibits antitumor activity in patients with -mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on -mutated thyroid cancer cells and its effect on the response of these cells to kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of -mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/AKT signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of -mutated thyroid cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes -mutant thyroid cancer cells to PLX4032 by inhibiting and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for -mutated thyroid cancers.
，作为最常见的基因改变，已成为甲状腺癌的主要治疗靶点。维莫非尼（PLX4032），一种激酶的特异性抑制剂，在具有 - 突变的甲状腺癌患者中表现出抗肿瘤活性。然而，PLX4032的临床益处通常受到短期反应和通过异质反馈机制获得性耐药的限制。双硫仑（DSF），一种戒酒药物，以铜（Cu）依赖的方式显示出强大的抗肿瘤功效。然而，其在甲状腺癌中的抗肿瘤活性及其对细胞对激酶抑制剂反应的影响仍不清楚。通过一系列体外和体内功能实验系统评估了DSF/Cu对 - 突变甲状腺癌细胞的抗肿瘤作用及其对这些细胞对激酶抑制剂PLX4032反应的影响。通过蛋白质印迹和流式细胞术分析探索了DSF/Cu对PLX4032致敏作用的分子机制。与单独的DSF治疗相比，DSF/Cu对 - 突变甲状腺癌细胞的增殖和集落形成表现出更强的抑制作用。进一步的研究表明，DSF/Cu通过ROS依赖的MAPK/ERK和PI3K/AKT信号通路抑制杀死甲状腺癌细胞。我们的数据还表明，DSF/Cu显著增加了 - 突变甲状腺癌细胞对PLX4032的反应。从机制上讲，DSF/Cu通过以ROS依赖的方式抑制 和AKT，随后缓解MAPK/ERK和PI3K/AKT途径的反馈激活，使 - 突变甲状腺癌细胞对PLX4032敏感。这项研究不仅暗示了DSF/Cu在癌症治疗中的潜在临床应用，还为 - 突变甲状腺癌提供了一种新的治疗策略。
