Electron paramagnetic resonance study of peripheral blood mononuclear cells from patients with refractory solid tumors treated with Triapine((R))

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Room K4/554, Madison, WI 53792, USA.
Journal of Inorganic Biochemistry (Impact Factor: 3.44). 05/2008; 102(4):693-8. DOI: 10.1016/j.jinorgbio.2007.10.013
Source: PubMed


The metal chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase. EPR spectra consistent with signals from Fe-transferrin, heme, and low-spin iron or cupric ion were observed in peripheral blood mononuclear cells (PBMCs) obtained from patients treated with Triapine. One signal that is unequivocally identified is the signal for Fe-transferrin. It is hypothesized that Fe uptake is blocked by reactive oxygen species generated by FeT(2) or CuT that damage transferrin or transferrin receptor. A potential source for the increase in the heme signal is cytochrome c released from the mitochondria. These results provide valuable insight into the in vivo mechanism of action of Triapine.

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Available from: George Wilding, Apr 20, 2015
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    • "Such systems give rise to low crystalline fields, hence iron is in the high-spin state S = 5/2. In some works [8, 9, 11, 18–20] this signal is a single peak and in others [6, 7, 13, 17] it shows a complex. Most authors have interpreted this signal as originating from Fe3+ in transferrin [7–9, 11–20]. "
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    • "However, the ability of chelators to inhibit RR activity is well documented (Cooper et al., 1996). From previous studies (Finch et al., 1999; Kolesar et al., 2008), it remains unclear whether chelation alone is totally responsible for inhibiting RR. For example, the thiosemicarbazone-based chelator, Triapine, is a more active RR inhibitor when added to cells as an iron or copper complex than the ligand alone (Finch et al., 1999). "
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    ABSTRACT: Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (n = 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 ± 9%; n = 3) and inhibited thioredoxin reductase activity (62 ± 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP(total) ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems.
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