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Protection of Zinc against Tumor Necrosis Factor–Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

¹ Department for Molecular Biomedical Research, VIB; ² Department of Molecular Biology, Ghent University, Ghent, Belgium; ³ Department of Molecular Biology and Immunology, National Institute of Agrobiological Sciences, Ibaraki, Japan; and ⁴ Institute of Immunology, Biological Sciences Research Center Alexander Fleming, Vari, Greece

Requests for reprints: Claude Libert, Department for Molecular Biomedical Research, VIB, Technologiepark 927, B-9052 Ghent, Belgium. Phone: 32-9-331-3700; Fax: 32-9-331-3609; E-mail: Claude.Libert{at}dmbr.UGent.be.

Tumor necrosis factor (TNF)–induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO₄ to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred dose-responsive protection against TNF-induced hypothermia, systemic induction of interleukin-6 and NO_x, as well as against TNF-induced bowel cell death and death of the organism. The protective effect of zinc was completely absent in mice deficient in the major HSP70-inducible gene, hsp70.1, whereas transgenic mice constitutively expressing the human HSP70.A gene, under control of a ß-actin promoter, was also protected against TNF, indicating that an increase in HSP70 is necessary and sufficient to confer protection. The therapeutic potential of the protection induced by ZnSO₄ was clearly shown in a TNF/IFN–based antitumor therapy using three different tumor models. In hsp70.1 wild-type mice, but not in hsp70.1-deficient mice, zinc very significantly protected against lethality but left the antitumor effect intact. We conclude that zinc protects against TNF in a HSP70-dependent way and that protection by zinc could be helpful in developing a safer anticancer therapy with TNF/IFN. [Cancer Res 2007;67(15):7301–7]

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