The following is a summary of “Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy,” published in the January 2024 issue of Oncology by Alcalá et al.
In their preceding investigations, researchers unveiled oxidative phosphorylation (OXPHOS) as the pivotal pathway fueling the energetic demands of pancreatic cancer stem cells (CSCs), signifying OXPHOS as a vulnerable point for these highly tumorigenic cells. Unfortunately, therapeutic strategies specifically targeting OXPHOS in CSCs have been lacking. To address this, the study group assessed the safety and anti-CSC efficacy of a ruthenium complex, denoted Ru1, featuring bipyridine and terpyridine ligands with one coordination labile position. Their evaluations encompassed primary pancreatic cancer cultures and in vivo studies using eight patient-derived xenografts (PDXs). Employing RNAseq analysis and mitochondria-specific molecular assays, investigators sought to elucidate the mechanism of Ru1 action.
Their findings underscore the capacity of Ru1 to impede CSC OXPHOS function in vitro, showcasing robust anti-cancer efficacy with minimal toxicity across a diverse panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistically, their investigations propose that Ru1 achieves this effect by binding to the D-loop region of mitochondrial DNA in CSCs, thereby inhibiting transcription associated with OXPHOS complexes. This inhibition leads to a reduction in mitochondrial oxygen consumption, membrane potential, and ATP production—essential processes for CSCs, which heavily rely on mitochondrial respiration.
In conclusion, the coordination complex Ru1 emerges not only as a promising new anti-cancer agent but also as a molecular tool enabling a detailed exploration of the role of OXPHOS in CSCs. Their results demonstrating the compound’s safety, low toxicity, and high efficacy in vivo are particularly encouraging. These findings unveil unprecedented mechanistic possibilities for combatting various cancer types by selectively targeting CSC OXPHOS, paving the way for innovative therapeutic strategies in cancer treatment.
Source: jeccr.biomedcentral.com/articles/10.1186/s13046-023-02931-7
