This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Molle, W. Articles by Libert, C. Search for Related Content PubMed PubMed Citation Articles by Van Molle, W. Articles by Libert, C.

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]

This article has been cited by other articles:

				P. J. Smith, M. Wiltshire, E. Furon, J. H. Beattie, and R. J. Errington Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1399 - C1408. [Abstract] [Full Text] [PDF]