A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells
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...
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MDPI AG
2025-06-01
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| author | Yuhuan Wu Ziyao Chang Wenhao Wang Chuanbin Wu Xin Pan Zhengwei Huang |
| author_facet | Yuhuan Wu Ziyao Chang Wenhao Wang Chuanbin Wu Xin Pan Zhengwei Huang |
| author_sort | Yuhuan Wu |
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| description | 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)<sub>2</sub>] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)<sub>2</sub> exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)<sub>2</sub>@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)<sub>2</sub>, 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. |
| format | Article |
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| issn | 2218-273X |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-e612873124f144afb5e11ac603fd23622025-08-20T02:24:33ZengMDPI AGBiomolecules2218-273X2025-06-0115689510.3390/biom15060895A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma CellsYuhuan Wu0Ziyao Chang1Wenhao Wang2Chuanbin Wu3Xin Pan4Zhengwei Huang5School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, ChinaState 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, ChinaSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, ChinaState 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, ChinaCuproptosis, 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)<sub>2</sub>] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)<sub>2</sub> exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)<sub>2</sub>@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)<sub>2</sub>, 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.https://www.mdpi.com/2218-273X/15/6/895cuproptosiscopper ionophoreintracellular copper accumulationnanoshuttleB16 melanoma cells |
| spellingShingle | Yuhuan Wu Ziyao Chang Wenhao Wang Chuanbin Wu Xin Pan Zhengwei Huang A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells Biomolecules cuproptosis copper ionophore intracellular copper accumulation nanoshuttle B16 melanoma cells |
| title | A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells |
| title_full | A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells |
| title_fullStr | A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells |
| title_full_unstemmed | A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells |
| title_short | A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells |
| title_sort | novel copper ionophore nanoshuttle winged cu for inducing cuproptosis in b16 melanoma cells |
| topic | cuproptosis copper ionophore intracellular copper accumulation nanoshuttle B16 melanoma cells |
| url | https://www.mdpi.com/2218-273X/15/6/895 |
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