Together, these results suggest that patients undergoing Triapine treatment should be monitored for Fe depletion. All three of the chelators increased IRP RNA-binding activity, which suggests chelation of intracellular Fe pools. We demonstrated that Triapine has activity somewhat similar to that of DFO but is far less efficient than 311. 1) and shows high Fe chelation efficacy and antitumor activity (36, 37, 38, 39). This chelator has some structural similarity to thiosemicarbazones (see Fig. In the present study, we examined the Fe chelation efficacy and mechanism of action of Triapine compared with DFO and a novel chelator of the PIH class known as 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311). Dfo three kingdoms free#Furthermore, the Triapine Fe complex was shown to be redox active.Ĭonclusion: The cytotoxic mechanism of action of Triapine was different from that of DFO and 311, with the combined action of Fe chelation and free radical generation being involved. Complexation of Triapine with Fe had no appreciable effect on its antiproliferative activity, whereas addition of Fe totally inhibited the effects of DFO and 311. All three of the chelators showed greater activity against the proliferation of neoplastic than of normal cells, the effect of 311 and Triapine being similar and these two chelators being significantly ( P < 0.0001) more active than DFO. In terms of preventing 59Fe uptake from Tf, Triapine and DFO had similar activity, having far less efficacy than 311. Results: Triapine was twice as effective as DFO at mobilizing 59Fe from prelabeled cells but was much less efficient than 311. These studies have been performed using several neuroepithelioma and neuroblastoma cell lines and a variety of normal cell types including fibroblasts, umbilical vein endothelial cells, skeletal muscle cells, monocyte-derived macrophages, and bone marrow stem cells. Redox activity was determined by ascorbate oxidation, benzoate hydroxylation, plasmid DNA degradation, and the precipitation of cellular DNA. We assessed the effects of chelators on proliferation, Fe uptake, Fe efflux, the expression of cell cycle control molecules, and iron-regulatory protein-RNA-binding activity. This latter ligand was relevant to compare, because it is tridentate like Triapine and shares structural similarity. This is essential for understanding its mechanism of action and clinical effects.Įxperimental Design: We compared the effect of Triapine with DFO, and also with the novel Fe chelator, 311, which shows marked antiproliferative activity. This compound is a potential Fe chelator, but despite this, no investigations have examined its effect on cellular Fe metabolism. Recently, the potent inhibitor of ribonucleotide reductase, Triapine, has entered clinical trials as an anticancer agent. Purpose: Tumors are sensitive to iron (Fe) chelation therapy with the clinically used chelator desferrioxamine (DFO).
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