title: Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells.
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.
authors.affiliation: Department of Biology, University of Girona, Girona, Catalunya, Spain; Institut de Química Computacional i Catàlisi (IQCC), University of Girona, Girona, Catalunya, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Bártulos
authors.affiliation: Departament de Biologia Fonamental and Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Illes Balears, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Aceves-Luquero
authors.affiliation: Department of Chemistry, University of Girona, Girona, Catalunya, Spain.
authors.forename: Jamal
authors.initials: J
authors.lastname: Qualai
authors.affiliation: Department of Chemistry, University of Girona, Girona, Catalunya, Spain; Institut de Química Computacional i Catàlisi (IQCC), University of Girona, Girona, Catalunya, Spain.
authors.forename: Olaf
authors.initials: O
authors.lastname: Cussó
authors.affiliation: Department of Biology, University of Girona, Girona, Catalunya, Spain; Department of Chemistry, University of Girona, Girona, Catalunya, Spain.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Martínez
authors.affiliation: Departament de Biologia Fonamental and Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Illes Balears, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández de Mattos
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Catalunya, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Catalunya, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menéndez
authors.affiliation: Departament de Biologia Fonamental and Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Illes Balears, Spain.
authors.forename: Priam
authors.initials: P
authors.lastname: Villalonga
authors.affiliation: Department of Chemistry, University of Girona, Girona, Catalunya, Spain; Institut de Química Computacional i Catàlisi (IQCC), University of Girona, Girona, Catalunya, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Costas
authors.affiliation: Department of Chemistry, University of Girona, Girona, Catalunya, Spain; Institut de Química Computacional i Catàlisi (IQCC), University of Girona, Girona, Catalunya, Spain.
authors.forename: Xavi
authors.initials: X
authors.lastname: Ribas
authors.affiliation: Department of Biology, University of Girona, Girona, Catalunya, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
mesh_terms: D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005296:Ferrous Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D016877:Oxidants; D011725:Pyridines; D017382:Reactive Oxygen Species; D007501:Iron; C023666:pyridine