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- Title
Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors.
- Authors
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.
- 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.
- Subjects
RUTHENIUM; CANCER cells; CELL death; MITOCHONDRIA; SMALL molecules
- Publication
Cell Death Discovery, 2024, Vol 10, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-024-02033-z