학술논문
Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.
Document Type
Article
Author
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
Source
Subject
*CANCER stem cells
*RUTHENIUM compounds
*MITOCHONDRIAL DNA
*PANCREATIC cancer
*OXIDATIVE phosphorylation
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Language
ISSN
1756-9966
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. [ABSTRACT FROM AUTHOR]