title: Ferrocene-induced lymphocyte activation and anti-tumor activity is mediated by redox-sensitive signaling.
abstract: Ferrocene, a stable, synthetic, iron-containing compound induces in vitro and in vivo activation of mouse lymphocytes and macrophages. Ferrocene also has a marked antitumor effect in mice, upon its administration intraperitoneally and in drinking water. Ferrocene's antitumor activity is attributed to its immune-stimulatory property. This conclusion is supported by adoptive transfer experiments demonstrating that immune cells from ferrocene-treated tumor-bearing mice elicit an antitumor effect in mice not treated with ferrocene. We postulate that the immune stimulatory effect of ferrocene is mediated by redox-sensitive signaling such as activation of p21ras. This postulation is supported by the following findings: Ferrocene generates H2O2 by autooxidation; N-acetylcysteine, a free-radical scavenger, reduces its antitumor effect; and it stimulates GTPase activity catalyzed by pure recombinant p21ras and activates ERK 1/2 in wild Jurkat T cells but fails to do so in the Jurkat T cells expressing p21ras in which cysteine 118 was replaced by serine. Lastly, ferrocene activates and translocates NF-kappaB in human PBM, a pathway which is mediated by ras. It is most plausible that additional redox-sensitive signaling proteins mediate the biological effects of ferrocene.
authors.affiliation: Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center, Beilinson Campus, Petah-Tikva, 49100, Israel.
authors.forename: Riva
authors.initials: R
authors.lastname: Kovjazin
authors.forename: Tova
authors.initials: T
authors.lastname: Eldar
authors.forename: Miriam
authors.initials: M
authors.lastname: Patya
authors.forename: Alexey
authors.initials: A
authors.lastname: Vanichkin
authors.forename: Harry M
authors.initials: HM
authors.lastname: Lander
authors.forename: Abraham
authors.initials: A
authors.lastname: Novogrodsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D005296:Ferrous Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy; D000075163:Metallocenes; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; C004998:ferrocene