Ferrocene‐induced lymphocyte activation and antitumor activity is mediated by redox‐sensitive signaling

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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.