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钌（II）配合物作为线粒体破坏剂诱导的坏死性凋亡。

Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors.

作者信息

Gonçalves Joana, Amaral Joana D, Capela Rita, Perry Maria de Jesus, Braga Cláudia, Gaspar Maria Manuela, Piedade Fátima M, Bijlsma Lubertus, Roig Antoni, Pinto Sandra N, Moreira Rui, Florindo Pedro, Rodrigues Cecília M P

机构信息

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Instituto de Biofísica e Engenharia Biomédica, Faculty of Sciences, Universidade de Lisboa, Lisbon, Portugal.

出版信息

Cell Death Discov. 2024 May 28;10(1):261. doi: 10.1038/s41420-024-02033-z.

DOI:10.1038/s41420-024-02033-z
PMID:38806468
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11133381/
Abstract

Inducing necroptosis in cancer cells has emerged as an effective strategy to overcome drug resistance. However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death. Here we show that incorporating a methyltriazene moiety, a known alkylating warhead, confers superior mitochondrial-targeting properties and enhances cell death compared to amide-containing counterparts. Ru-hybrid TRZ2 exhibits also antitumor efficacy against in vivo drug-resistant cancer cells. Mechanistically, we demonstrate that Ru-TRZ hybrids induce apoptosis. In addition, by activating downstream RIPK3-driven cell death, TRZ2 proficiently restrains normal mitochondrial function and activity, leading to cancer cell necroptosis. Finally, TRZ2 synergizes anti-proliferative activity and cell death effects induced by conventional drugs. In conclusion, Ru-TRZ2 stands as a promising ruthenium-based chemotherapeutic agent inducing necroptosis in drug resistant cancer cells.

摘要

诱导癌细胞发生坏死性凋亡已成为克服耐药性的一种有效策略。然而，尽管有机小分子已为此目的得到广泛研究，但金属基化合物作为坏死性凋亡的触发因素却相对较少受到关注。钌（II）杂化化合物的开发，特别是那些含有三氮烯的化合物（Ru-TRZ），为调节坏死性细胞死亡开辟了一条新途径。在此，我们表明，与含酰胺的类似物相比，引入已知的烷基化弹头甲基三氮烯部分可赋予其卓越的线粒体靶向特性并增强细胞死亡。Ru-杂化TRZ2对体内耐药癌细胞也具有抗肿瘤功效。从机制上讲，我们证明Ru-TRZ杂化物可诱导凋亡。此外，通过激活下游RIPK3驱动的细胞死亡，TRZ2可有效抑制正常线粒体功能和活性，导致癌细胞坏死性凋亡。最后，TRZ2可增强传统药物诱导的抗增殖活性和细胞死亡效应。总之，Ru-TRZ2是一种有前景的基于钌的化疗药物，可诱导耐药癌细胞发生坏死性凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/95e0fc1aa948/41420_2024_2033_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/9336f62c707d/41420_2024_2033_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/e161485c7278/41420_2024_2033_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/c4192900c25e/41420_2024_2033_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/750ac5afed11/41420_2024_2033_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/4045210300b3/41420_2024_2033_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/95e0fc1aa948/41420_2024_2033_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/9336f62c707d/41420_2024_2033_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/e161485c7278/41420_2024_2033_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/c4192900c25e/41420_2024_2033_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/750ac5afed11/41420_2024_2033_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/4045210300b3/41420_2024_2033_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b7c/11133381/95e0fc1aa948/41420_2024_2033_Fig6_HTML.jpg

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本文引用的文献

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