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 b...

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Autores: 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
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2015
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/12220
Acesso em linha:http://hdl.handle.net/10256/12220
Access Level:Acceso aberto
Palavra-chave:Cèl·lules canceroses
Cancer cells
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spelling Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like CellsGonzález-Bártulos, MartaAceves Luquero, ClaraQualai, JamalCussó Forest, OlafMartínez Lorente, Mª ÁngelesFernández de Mattos, SilviaMenéndez Menéndez, Javier AbelVillalonga, PriamCostas Salgueiro, MiquelRibas Salamaña, XaviMassaguer i Vall-llovera, AnnaCèl·lules cancerosesCancer cellsDifferential 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 metallodrugsThis 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+IPublic Library of Science (PLoS)Ministerio de Ciencia e Innovación (Espanya)2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10256/12220http://hdl.handle.net/10256/12220PLoS One, 2015, vol. 10, núm. 9, p. e0137800Articles publicats (D-B)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0137800info:eu-repo/semantics/altIdentifier/eissn/1932-6203MICINN/PN 2010-2016/CSD2010-00065Attribution 3.0 Spainhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:10256/122202026-05-29T05:05:01Z
dc.title.none.fl_str_mv Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
title Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
spellingShingle Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
González-Bártulos, Marta
Cèl·lules canceroses
Cancer cells
title_short Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
title_full Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
title_fullStr Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
title_full_unstemmed Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
title_sort Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells
dc.creator.none.fl_str_mv 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
author González-Bártulos, Marta
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (Espanya)
dc.subject.none.fl_str_mv Cèl·lules canceroses
Cancer cells
topic Cèl·lules canceroses
Cancer cells
description 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
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/12220
http://hdl.handle.net/10256/12220
url http://hdl.handle.net/10256/12220
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0137800
info:eu-repo/semantics/altIdentifier/eissn/1932-6203
MICINN/PN 2010-2016/CSD2010-00065
dc.rights.none.fl_str_mv Attribution 3.0 Spain
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 3.0 Spain
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv PLoS One, 2015, vol. 10, núm. 9, p. e0137800
Articles publicats (D-B)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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repository.mail.fl_str_mv
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