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Research Articles: Therapeutics

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

¹ Departments of Pathology and Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and ² Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington

Requests for reprints: Wei-Qun Ding, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, BRC 409, Oklahoma City, OK 73104. Phone: 405-271-3828; Fax: 405-271-3190. E-mail: weiqun-ding{at}ouhsc.edu

Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-B activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways. [Mol Cancer Ther 2006;5(7):1864–72]

Received 2/ 3/06; revised 4/ 6/06; accepted 5/10/06.