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.
In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites
Eliška Potůčková,Jaroslav Roh,M. Macháček,S. Sahni,Ján Stariat,V. Šesták,Hana Jansová,P. Hašková,A. Jirkovská,K. Vávrová,P. Kovaříková,D. Kalinowski,D. Richardson,T. Šimůnek
Published 2015 in PLoS ONE
ABSTRACT
PUBLICATION RECORD
- Publication year
2015
- Venue
PLoS ONE
- Publication date
2015-10-13
- Fields of study
Biology, Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- 59fe-labeled transferrin uptake
An iron-uptake assay measuring cellular entry of radioactive iron delivered by transferrin.
Aliases: 59Fe uptake from 59Fe-labeled transferrin, 59Fe uptake
- amidrazone metabolite
A phase I metabolite of Bp4eT containing an amidrazone moiety.
- apoptosis
Programmed cell death measured as a downstream cellular response in the tested cells.
- bp4et
A 2-benzoylpyridine thiosemicarbazone ligand studied here as the parent anti-cancer iron chelator.
Aliases: 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone
- iron redox cycling
A chemical process in which iron changes oxidation state repeatedly and can alter iron reactivity and availability.
Aliases: redox cycling of iron
- labile intracellular iron pools
The readily exchangeable cellular iron pool that can be mobilized by iron-binding compounds.
Aliases: intracellular iron pools, labile iron pool
- mcf-7 cells
A human breast adenocarcinoma cell line used as a cancer-cell model in the experiments.
Aliases: MCF-7 human breast adenocarcinoma cells, MCF-7 human breast adenocarcinoma
- mitochondrial depolarization
Loss of mitochondrial membrane potential, used as a readout of mitochondrial dysfunction.
- semicarbazone metabolite
A phase I metabolite of Bp4eT containing a semicarbazone moiety.
- s phase cell cycle arrest
A cell-cycle state in which cells accumulate in S phase during DNA synthesis.
Aliases: S-phase arrest
REFERENCES
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