Pro-oxidant activity of amine-pyridine-based iron complexes efficiently kills cancer and cancer stem-like cells

Show simple item record González Bártulos, Marta Aceves Luquero, Clara Qualai, Jamal Cussó Forest, Olaf Martínez, María Ángeles Fernández de Mattos, Silvia Elena Menéndez, Javier Abel De Villalonga Smith, Priam Francesc Costas Salgueiro, Miquel Ribas Salamaña, Xavi Massaguer, Anna 2016-02-01T10:04:05Z 2016-02-01T10:04:05Z 2015-09-14
dc.identifier.citation 1932-6203
dc.description.abstract Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe(II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides. Five of these Fe(II)-complexes and the corresponding aminopyridine ligands were selected to evaluate their anticancer properties. We found that the iron complexes failed to display any relevant activity, while the corresponding ligands exhibited significant antiproliferative activity. Among the ligands, none of which were hemolytic, compounds 1, 2 and 5 were cytotoxic in the low micromolar range against a panel of molecularly diverse human cancer cell lines. Importantly, the cytotoxic activity profile of some compounds remained unaltered in epithelial-to-mesenchymal (EMT)-induced stable populations of cancer stem-like cells, which acquired resistance to the well-known ROS inducer doxorubicin. Compounds 1, 2 and 5 inhibited the clonogenicity of cancer cells and induced apoptotic cell death accompanied by caspase 3/7 activation. Flow cytometry analyses indicated that ligands were strong inducers of oxidative stress, leading to a 7-fold increase in intracellular ROS levels. ROS induction was associated with their ability to bind intracellular iron and generate active coordination complexes inside of cells. In contrast, extracellular complexation of iron inhibited the activity of the ligands. Iron complexes showed a high proficiency to cleave DNA through oxidative-dependent mechanisms, suggesting a likely mechanism of cytotoxicity. In summary, we report that, upon chelation of intracellular iron, the pro-oxidant activity of amine-pyrimidine-based iron complexes efficiently kills cancer and cancer stem-like cells, thus providing functional evidence for an efficient family of redox-directed anti-cancer metallodrugs.
dc.language.iso eng
dc.publisher Public Library of Science
dc.relation.isformatof Reproducció del document publicat a:
dc.relation.ispartof Plos One, 2015, vol. 10, num. 9, p. e0137800
dc.rights cc-by (c) González Bártulos, Marta et al., 2015
dc.subject.classification Biologia
dc.subject.classification Ciències de la salut
dc.subject.other Biology
dc.subject.other Medical sciences
dc.title Pro-oxidant activity of amine-pyridine-based iron complexes efficiently kills cancer and cancer stem-like cells
dc.type info:eu-repo/semantics/article
dc.type info:eu-repo/semantics/publishedVersion 2016-02-01T10:04:06Z
dc.subject.keywords Hierro
dc.subject.keywords Cáncer
dc.rights.accessRights info:eu-repo/semantics/openAccess

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cc-by (c) González Bártulos, Marta et al., 2015 Except where otherwise noted, this item's license is described as cc-by (c) González Bártulos, Marta et al., 2015

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