Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors

  • Cell Death Discov. 2024 May 28;10(1):261. doi: 10.1038/s41420-024-02033-z.
Joana Gonçalves  1 ,  Joana D Amaral  1 ,  Rita Capela  1 ,  Maria de Jesus Perry  1 ,  Cláudia Braga  1 ,  Maria Manuela Gaspar  1  2 ,  Fátima M Piedade  3  4 ,  Lubertus Bijlsma  5 ,  Antoni Roig  5 ,  Sandra N Pinto  6 ,  Rui Moreira  1 ,  Pedro Florindo  1 ,  Cecília M P Rodrigues  7
Affiliations
  • 1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
  • 2. Instituto de Biofísica e Engenharia Biomédica, Faculty of Sciences, Universidade de Lisboa, Lisbon, Portugal.
  • 3. Departamento de Química e Bioquímica, Faculty of Sciences, Universidade de Lisboa, Lisbon, Portugal.
  • 4. Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
  • 5. Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, Castelló, Spain.
  • 6. iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
  • 7. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. [email protected].
PMID: 38806468 DOI: 10.1038/s41420-024-02033-z
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.

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