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

• Published in: Journal of experimental & clinical cancer research 2024-01, Vol.43 (1), p.33-27, Article 33
• Main Authors: Alcalá, Sonia, Villarino, Lara, Ruiz-Cañas, Laura, Couceiro, José R, Martínez-Calvo, Miguel, Palencia-Campos, Adrián, Navarro, Diego, Cabezas-Sainz, Pablo, Rodriguez-Arabaolaza, Iker, Cordero-Barreal, Alfonso, Trilla-Fuertes, Lucia, Rubiolo, Juan A, Batres-Ramos, Sandra, Vallespinos, Mireia, González-Páramos, Cristina, Rodríguez, Jéssica, Gámez-Pozo, Angelo, Vara, Juan Ángel Fresno, Fernández, Sara Fra, Berlinches, Amparo Benito, Moreno-Mata, Nicolás, Redondo, Ana María Torres, Carrato, Alfredo, Hermann, Patrick C, Sánchez, Laura, Torrente, Susana, Fernández-Moreno, Miguel Ángel, Mascareñas, José L, Sainz, Jr, Bruno
• Format: Article
• Language: English
• Subjects: Anti-cancer agents; Aqueous solutions; Cancer; Cancer stem cells; Cancer therapies; Care and treatment; Colon cancer; Colorectal cancer; Ethylenediaminetetraacetic acid; Fatalities; Genetic transcription; Humans; Mitochondria - metabolism; Mitochondrial DNA; Neoplastic Stem Cells - metabolism; Oxidative Phosphorylation; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Penicillin; Respiration; RNA sequencing; Ruthenium; Ruthenium - pharmacology; Ruthenium complexes; Scientific equipment and supplies industry; Spheres; Stem cells; Toxicity; Tumors
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-023-02931-7

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. 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. 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. 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.