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

Abstract

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 doseresponsive 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 B-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/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]

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

“…For example, cellular level manipulation of zinc accumulation to toxic levels, via analogs of zinc ionophore 1-hydroxypyridine-2-thione, is currently being considered as a novel approach in cancer therapeutics (25). Furthermore, exogenously supplied zinc may extend the application of the antitumor agent tumor necrosis factor (TNF) by inducing a protective effect against the generation of TNF-induced inflammation in at-risk organs (49). The principle is to use zinc to induce the heat shock protein 70 in such organs, including the gastrointestinal tract, thereby preventing a potentially lethal systemic inflammatory response by reducing cytokine liberation (49).…”

“…Furthermore, exogenously supplied zinc may extend the application of the antitumor agent tumor necrosis factor (TNF) by inducing a protective effect against the generation of TNF-induced inflammation in at-risk organs (49). The principle is to use zinc to induce the heat shock protein 70 in such organs, including the gastrointestinal tract, thereby preventing a potentially lethal systemic inflammatory response by reducing cytokine liberation (49). Protection against TNFinduced lethality by zinc appears to be independent of MT (51), suggesting that any modulation by MT of zinc ion availability at the cellular level is limited.…”

“…Thus the impact of MT overexpression on normal growth control or protection from zinc toxicity would appear to be complex (36). Understanding the interplay between zincinduced stress responses and MT expression is relevant to a current rationale for the use of a managed supply of zinc in providing safer anticancer therapies (49,51). Here we have focused on the role of the innate expression of MT on cell proliferation, protection from zinc toxicity, and the steady-state levels of available intracellular Zn 2ϩ (37).…”

Gut epithelial inducible heat-shock proteins and their modulation by diet and the microbiota

“…156 In another study, zinc sulfate (25 mM, in water for 7 days) protected mice against TNF-induced lethal inflammation through an iHSP70-dependent mechanism. 157 Zinc oxide (0.05-1 mM) can upregulate various heat-stress genes, including the Hsp70 gene in swine IPEC-J2 cells. 158,159 However, high supplementation with zinc (as zinc oxide, 2200 mg of zinc per kilogram of diet for 1 week), despite its anti-inflammatory effects, did not influence gut epithelial iHSPs in pigs.…”

Inhibitory effects of zinc hyaluronate on synoviocyte growth and matrix metalloproteinase-9 activity

“…6 While most heavy metals are toxic, Zinc is safe for internal use. 12 Zinc is also known to play a regulatory role in the immune system; it can have anti-inflammatory effects, apparently as a consequence of direct interaction with cytokines secreted by monocytes. 13 Zinc protects against lipopolysaccharide (LPS) hepatotoxicity by inhibiting TNF production.…”