Protection of zinc against tumor necrosis factor-induced lethal inflammation depends on heat shock protein 70 and allows safe antitumor therapy

Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO(4) to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred dose-...

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Published in:	Cancer research (Chicago, Ill.) Vol. 67; no. 15; pp. 7301 - 7307
Main Authors:	VAN MOLLE, Wim, VAN ROY, Maarten, VAN BOGAERT, Tom, DEJAGER, Lien, VAN LINT, Philippe, VANLAERE, Ineke, SEKIKAWA, Kenji, KOLLIAS, George, LIBERTL, Claude
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-08-2007
Subjects:	Animals Antineoplastic agents Antineoplastic Agents - therapeutic use Antiviral Agents - therapeutic use Biological and medical sciences Dose-Response Relationship, Drug Female HSP70 Heat-Shock Proteins - genetics HSP70 Heat-Shock Proteins - metabolism Humans Hypothermia Inflammation - metabolism Inflammation - pathology Inflammation - prevention & control Interferon-gamma - therapeutic use Interleukin-6 - metabolism Intestine, Small - pathology Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Necrosis Neoplasms, Experimental - drug therapy Pharmacology. Drug treatments Survival Rate Tumor Cells, Cultured Tumor Necrosis Factor-alpha - toxicity Tumors Zinc Sulfate - therapeutic use Antineoplastic agent Treatment Tumor necrosis factor Mortality Cytokine Heat shock protein Heat shock protein 70 Inflammation Zinc
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Summary:	Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO(4) 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 beta-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 ZnSO(4) was clearly shown in a TNF/IFNgamma-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/IFNgamma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-06-4010