{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:23:24Z","timestamp":1791033804135,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["21ek0109495h0001"],"award-info":[{"award-number":["21ek0109495h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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\u2010targeting moiety triphenylphosphonium (TPP), NX\u2013TPP and CFX\u2013TPP, to enhance mitochondrial delivery and examined their anticancer efficacy. NX\u2013TPP and CFX\u2013TPP markedly reduced the antibacterial activity, although CFX\u2013TPP was more active than NX\u2013TPP. However, both NX\u2013TPP and CFX\u2013TPP significantly induced cell death in colon HT\u201029, pancreatic MIAPaCa\u20102, and other cancer cells but not in non\u2010cancerous cells including normal dermal fibroblasts and human vascular endothelial cells at a comparative level. NX\u2013TPP induced necrosis\u2010like cell death characterized by cell membrane ballooning and rupture. Mechanistically, NX\u2013TPP 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\u2013TPP inhibited tumor growth in HT\u201029 and MIAPaCa\u20102 xenograft mouse models without any apparent adverse effects. These results suggest that mtDNA replication\u2010targeting quinolone derivatives, termed MitoQNs, that exhibit reduced antibacterial activity, thereby decreasing antibiotic resistance induction, and enhanced anticancer efficacy, are candidate drugs for cancer therapy.<\/jats:p>","DOI":"10.1111\/cas.70199","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:56:49Z","timestamp":1758088609000},"page":"3431-3441","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Anticancer Effect of the Triphenylphosphonium\u2010Conjugated Quinolone Antibiotics Targeting Mitochondrial\n                    <scp>DNA<\/scp>\n                    Replication"],"prefix":"10.1111","volume":"116","author":[{"given":"Yuming","family":"Qiao","sequence":"first","affiliation":[{"name":"Division of Innovative Cancer Therapeutics Chiba Cancer Center Research Institute  Chiba Japan"},{"name":"Graduate School of 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