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CELLULAR AND MOLECULAR

Clioquinol Promotes Cancer Cell Toxicity through Tumor Necrosis Factor Release from Macrophages

Centre for Neuroscience and Department of Pathology, University of Melbourne, Victoria, Australia (T.D., G.F., A.C., P.J.C., A.R.W.); and Mental Health Research Institute, Parkville, Victoria, Australia. (T.D., G.F., A.C., P.J.C., A.R.W.)

Copper has an important role in cancer growth, angiogenesis, and metastasis. Previous studies have shown that cell-permeable metal ligands, including clioquinol (CQ) and pyrrolidine dithiocarbamate, inhibit cancer cell growth in cell culture and in vivo. The mechanism of action has not been fully determined but may involve metal-mediated inhibition of cancer cell proteasome activity. However, these studies do not fully account for the ability of cell-permeable metal ligands to inhibit cancer cell growth without affecting normal cells. In this study, we examined the effect of CQ on macrophage-mediated inhibition of HeLa cancer cell growth in vitro. When CQ was added to RAW 264.7 macrophage-HeLa cell cocultures, a substantial increase in HeLa cell toxicity was observed compared with CQ treatment of HeLa cells cultured alone. Transfer of conditioned medium from CQ-treated macrophages to HeLa cells also induced HeLa cell toxicity, demonstrating the role of secreted factors in the macrophage-mediated effect. Further investigation revealed that CQ induced copper-dependent activation of macrophages and release of tumor necrosis factor (TNF) .In studies with recombinant TNF, we showed that the level of TNF released by CQ-treated macrophages was sufficient to induce HeLa cell toxicity. Moreover, the toxic effect of conditioned medium from CQ-treated macrophages could be prevented by addition of neutralizing antibodies to TNF. These studies demonstrate that CQ can induce cancer cell toxicity through metal-dependent release of TNF from macrophages. Our results may help to explain the targeted inhibition of tumor growth in vivo by CQ.

Address correspondence to: Dr. Anthony R. White, Centre for Neuroscience and Department of Pathology, University of Melbourne, Victoria, Australia 3010. E-mail: arwhite{at}unimelb.edu.au

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