Anticancer Effect of the Triphenylphosphonium‐Conjugated Quinolone Antibiotics Targeting Mitochondrial DNA Replication

Antibacterial quinolones are widely used to treat bacterial infections in humans. They inhibit bacterial DNA gyrase and topoisomerase IV, whose analogous enzymes are present in mammalian mitochondria. Quinolones inhibit mitochondrial topoisomerases, thereby leading to mitochondrial DNA (mtDNA) replication suppression and cancer cell death. Meanwhile, high concentrations of quinolones are required to induce cancer cell death, possibly owing to poor delivery to the mitochondria. In this study, we synthesized nalidixic acid (NA) and ciprofloxacin (CFX) conjugated with the mitochondria‐targeting moiety triphenylphosphonium (TPP), NX–TPP and CFX–TPP, to enhance mitochondrial delivery and examined their anticancer efficacy. NX–TPP and CFX–TPP markedly reduced the antibacterial activity, although CFX–TPP was more active than NX–TPP. However, both NX–TPP and CFX–TPP significantly induced cell death in colon HT‐29, pancreatic MIAPaCa‐2, and other cancer cells but not in non‐cancerous cells including normal dermal fibroblasts and human vascular endothelial cells at a comparative level. NX–TPP induced necrosis‐like cell death characterized by cell membrane ballooning and rupture. Mechanistically, NX–TPP was efficiently incorporated into the mitochondria, leading to increased mitochondrial reaction oxygen species (mtROS) generation and mitophagy, and decreased mtDNA copy number and mitochondrial respiration. NX–TPP inhibited tumor growth in HT‐29 and MIAPaCa‐2 xenograft mouse models without any apparent adverse effects. These results suggest that mtDNA replication‐targeting quinolone derivatives, termed MitoQNs, that exhibit reduced antibacterial activity, thereby decreasing antibiotic resistance induction, and enhanced anticancer efficacy, are candidate drugs for cancer therapy.