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-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.
Van Molle
Wim
W
Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
Van Roy
Maarten
M
Van Bogaert
Tom
T
Dejager
Lien
L
Van Lint
Philippe
P
Vanlaere
Ineke
I
Sekikawa
Kenji
K
Kollias
George
G
Libert
Claude
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007035:Hypothermia; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000188:drug therapy; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D019287:Zinc Sulfate / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C081884:heat-shock protein 70.1; D019287:Zinc Sulfate; D007371:Interferon-gamma