Wu Yuhuan, Chang Ziyao, Wang Wenhao, Wu Chuanbin, Pan Xin, Huang Zhengwei
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Biomolecules. 2025 Jun 18;15(6):895. doi: 10.3390/biom15060895.
Cuproptosis, a newly discovered copper-dependent programmed cell death pathway, represents a promising approach for anticancer therapy. However, the efficacy of cuproptosis critically depends on intracellular copper accumulation. Traditional copper ionophores have limited therapeutic efficacy due to their reliance on serum copper levels. Therefore, the development of novel copper ionophores to enhance intracellular copper levels is urgently needed. In this study, we targeted a melanoma model and pioneered the application of Bis(2-hydroxyethyl)dithiocarbamic acid copper(II) [Cu(HEDTC)] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC) exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC), as a novel copper ionophore, significantly enhanced the copper level in B16 melanoma cells. Upon cellular internalization, CS NM underwent degradation and released copper ions, which subsequently triggered cuproptosis by causing abnormal aggregation of mitochondrial lipoylated proteins. This study provides a new experimental foundation and potential therapeutic strategy for cuproptosis-based cancer treatment.
铜死亡是一种新发现的依赖铜的程序性细胞死亡途径，是一种很有前景的抗癌治疗方法。然而，铜死亡的疗效关键取决于细胞内铜的积累。传统的铜离子载体由于依赖血清铜水平，治疗效果有限。因此，迫切需要开发新型铜离子载体以提高细胞内铜水平。在本研究中，我们针对黑色素瘤模型，率先应用双（2-羟乙基）二硫代氨基甲酸铜（II）[Cu（HEDTC）]作为高效铜离子载体，诱导B16黑色素瘤细胞发生铜死亡。与传统铜离子载体相比，Cu（HEDTC）表现出卓越的细胞内铜递送效率，从而增强了铜死亡的诱导。我们进一步构建了Cu（HEDTC）@Soluplus纳米胶束（CS NM）系统，旨在破坏肿瘤细胞中的铜离子稳态并放大铜死亡。在该系统中，Cu（HEDTC）作为新型铜离子载体，显著提高了B16黑色素瘤细胞中的铜水平。细胞内化后，CS NM发生降解并释放铜离子，随后通过导致线粒体脂酰化蛋白异常聚集触发铜死亡。本研究为基于铜死亡的癌症治疗提供了新的实验基础和潜在治疗策略。
