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Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells

Differential redox homeostasis in normal and malignant cells suggests that pro-oxidantinduced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a prooxidant 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 redoxdirected anti-cancer metallodrugs

This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO), CONSOLIDER-INGENIO 2010 CSD2010-00065, and from the Ministerio de Ciencia e Innovación (MICINN), SAF2012-38914, Plan Nacional de I+D+I

PLoS One, 2015, vol. 10, núm. 9, p. e0137800

Public Library of Science (PLoS)

Author: González-Bártulos, Marta
Aceves-Luquero, Clara
Qualai, Jamal
Cussó Forest, Olaf
Martínez Lorente, Mª Ángeles
Fernández de Mattos, Silvia
Menéndez Menéndez, Javier Abel
Villalonga, Priam
Costas Salgueiro, Miquel
Ribas Salamaña, Xavi
Massaguer i Vall-llovera, Anna
Date: 2015
Abstract: Differential redox homeostasis in normal and malignant cells suggests that pro-oxidantinduced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a prooxidant 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 redoxdirected anti-cancer metallodrugs
This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO), CONSOLIDER-INGENIO 2010 CSD2010-00065, and from the Ministerio de Ciencia e Innovación (MICINN), SAF2012-38914, Plan Nacional de I+D+I
Format: application/pdf
ISSN: 1932-6203
Document access: http://hdl.handle.net/10256/12220
Language: eng
Publisher: Public Library of Science (PLoS)
Collection: MICINN/PN 2010-2016/CSD2010-00065
Reproducció digital del document publicat a: http://dx.doi.org/10.1371/journal.pone.0137800
Articles publicats (D-B)
Is part of: PLoS One, 2015, vol. 10, núm. 9, p. e0137800
Rights: Attribution 3.0 Spain
Rights URI: http://creativecommons.org/licenses/by/3.0/es/
Subject: Cèl·lules canceroses
Cancer cells
Title: Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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