Abstract
Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.
Highlights
Iron is an essential cofactor for the activity of many enzymes crucial for cellular proliferation, including ribonucleotide reductase, which catalyzes the rate-limiting step in DNA synthesis [1]
As iron chelation is a key feature in the mechanism of action of benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), we examined the ability of Bp4eT and its metabolites to: (i) bind iron doi:10.1371/journal.pone.0139929.g001
Bp4eT was synthesized according to Kalinowski et al [9] and its metabolites were synthesized as described by Stariat et al [17,18]
Summary
Iron is an essential cofactor for the activity of many enzymes crucial for cellular proliferation, including ribonucleotide reductase, which catalyzes the rate-limiting step in DNA synthesis [1]. The thiosemicarbazone class of iron chelators have shown high anti-neoplastic efficiency in both in vitro and in vivo studies and some agents are in phase I and II clinical trials [4,5,6,7]. It was later demonstrated to be an iron chelator that possessed a low, positive Fe3+/2+ redox potential [9], which resulted in the formation of toxic reactive oxygen species (ROS) both in solution [9] and in cancer cells [10]. Bp4eT showed high anti-proliferative activity against human SK-N-MC neuroepithelioma cells with low toxicity to normal human MRC-5 fibroblasts [10]. Apart from its anti-cancer activity, Bp4eT showed potent inhibition of HIV-1 transcription with efficacy comparable to that of a clinically used anti-retroviral agent, roscovitin, and exhibited low cytotoxicity in the human T cell lymphoblast-like cell line, CCRF-CEM [11]
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