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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Research

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy

Authors: Sonia Alcalá, Lara Villarino, Laura Ruiz-Cañas, José R. Couceiro, Miguel Martínez-Calvo, Adrián Palencia-Campos, Diego Navarro, Pablo Cabezas-Sainz, Iker Rodriguez-Arabaolaza, Alfonso Cordero-Barreal, Lucia Trilla-Fuertes, Juan A. Rubiolo, Sandra Batres-Ramos, Mireia Vallespinos, Cristina González-Páramos, Jéssica Rodríguez, Angelo Gámez-Pozo, Juan Ángel Fresno Vara, Sara Fra Fernández, Amparo Benito Berlinches, Nicolás Moreno-Mata, Ana María Torres Redondo, Alfredo Carrato, Patrick C. Hermann, Laura Sánchez, Susana Torrente, Miguel Ángel Fernández-Moreno, José L. Mascareñas, Bruno Sainz Jr.

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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Abstract

Background

Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.

Methods

The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.

Results

We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.

Conclusions

Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.
Appendix
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Metadata
Title
Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy
Authors
Sonia Alcalá
Lara Villarino
Laura Ruiz-Cañas
José R. Couceiro
Miguel Martínez-Calvo
Adrián Palencia-Campos
Diego Navarro
Pablo Cabezas-Sainz
Iker Rodriguez-Arabaolaza
Alfonso Cordero-Barreal
Lucia Trilla-Fuertes
Juan A. Rubiolo
Sandra Batres-Ramos
Mireia Vallespinos
Cristina González-Páramos
Jéssica Rodríguez
Angelo Gámez-Pozo
Juan Ángel Fresno Vara
Sara Fra Fernández
Amparo Benito Berlinches
Nicolás Moreno-Mata
Ana María Torres Redondo
Alfredo Carrato
Patrick C. Hermann
Laura Sánchez
Susana Torrente
Miguel Ángel Fernández-Moreno
José L. Mascareñas
Bruno Sainz Jr.
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-023-02931-7

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