Ferrocene‐induced lymphocyte activation and antitumor 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.

Complexes of dichloro[2-(dimethylaminomethyl)phenyl-C1,N]gold(III), [Au(damp-C1,N)Cl2], with formylferrocene thiosemicarbazones: synthesis, structure and cytotoxicity

“…This effect probably results from an immune-stimulatory property of the organometallic compound [10].…”

Ferrocene‐modified thiopyrimidines: synthesis, enantiomeric resolution, antitumor activity

“…[11] Later A. Novogrodsky et al published results on the antitumor activity of ferrocene. [21] At small daily doses of 0.05 and 0.20 mg kg −1 the maximal effect of tumor growth inhibition was achieved on B16 melanoma in mice. At the same time at higher doses, 1.0 and 5.0 mg kg −1 , the effects of ferrocene were significantly lower.…”

26 Fe The Use of Iron‐Based Drugs in Medicine

“…57 The anti-tumour effect was observed at very low doses (0.05-0.2 mg/kg) which was about 2000 times less than the LD 50 of ferrocene. They proposed that the anti-tumour effect of ferrocene was mediated by immune stimulation, possibly against a target like p21 ras which is activated by redox signalling.…”