title: Anticancer activity of the antibiotic clioquinol.
abstract: Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC(50) values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. weiqun-ding@ouhsc.edu
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Vaught
authors.forename: Hanako
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D000072105:Superoxide Dismutase-1; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; C000606290:SOD1 protein, human; D007464:Clioquinol; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D015032:Zinc