Tailored ruthenium complexes target pancreatic cancer stem cell oxidative phosphorylation through inhibition of mitochondrial DNA transcription

Despite their well-known secondary toxic side-effects, platinum-based compounds continue to be among the most commonly used anti-cancer agents. While there have been efforts to develop alternative, more selective metallodrugs, success has been very limited. We now report that a ruthenium complex (Ru1), featuring bipyridine and terpyridine ligands, and one available coordination position, presents excellent anti-cancer properties across a panel of PDX models of pancreatic and colorectal cancer, with very low toxicity. Mechanistic studies indicate that Ru1 works by inhibiting mitochondrial respiration in cancer stem cells (CSC), likely via binding to accessible guanines in the D-loop region of their mitochondrial DNA