title: Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells.
abstract: The synthesis and the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen-like complex 2 and their oxidized quinone methide (QM) derivatives, 1-QM and 2-QM, are reported. Inhibition of purified thioredoxin reductase (TrxR) is observed with 1 and 2 only after their enzymatic oxidation by the hydrogen peroxide/horseradish peroxidase (H2O2/HRP) system with IC50 of 2.4 and 1.2μM respectively. However, this inhibition is larger than that obtained with the corresponding quinone methides (IC50=5.4μM for 1-QM and 3.6μM for 2-QM). The UV-Vis spectra of 1 or 2 incubated in the presence of H2O2/HRP show that the species generated is not a quinone methide, but probably the corresponding cation. In Jurkat cells, 2 shows high toxicity (IC50=7.4μM), while 1 is less effective (IC50=42μM). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition with 15μM) while the inhibition induced by 1 is much weaker (about 30% inhibition with 50μM). This strong inhibition of TrxR by 2 leads to accumulation of thioredoxin and peroxiredoxin 3 in oxidized form and to a decrease of the mitochondrial membrane potential (MMP). These results show that cytotoxicity of the osmocifens depends on their oxidation within the cell and that inhibition of thioredoxin reductase by oxidized species is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.
authors.affiliation: Istituto di Neuroscienze (CNR) Sezione di Padova, c/o Dipartimento di Scienze Biomediche, Via Ugo Bassi 58/b, 35131 Padova, Italy; Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Scalcon
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 place Jussieu, F-75005 Paris, France.
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 place Jussieu, F-75005 Paris, France; PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005 Paris, France; Division of Chemistry & Biological Chemistry, Nanyang Technological University, 21 Nanyang Ling, 637371, Singapore.
authors.forename: Hui Zhi Shirley
authors.initials: HZ
authors.lastname: Lee
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folda
authors.affiliation: Istituto di Neuroscienze (CNR) Sezione di Padova, c/o Dipartimento di Scienze Biomediche, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bindoli
authors.affiliation: Division of Chemistry & Biological Chemistry, Nanyang Technological University, 21 Nanyang Ling, 637371, Singapore.
authors.forename: Weng Kee
authors.initials: WK
authors.lastname: Leong
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 place Jussieu, F-75005 Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Salmain
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 place Jussieu, F-75005 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 place Jussieu, F-75005 Paris, France; PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005 Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D045563:Indolequinones / Q000737:chemistry; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D061105:Peroxiredoxin III / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D013629:Tamoxifen / Q000737:chemistry*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005296:Ferrous Compounds; D045563:Indolequinones; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C514120:ferrocifen; D013629:Tamoxifen; C068040:quinone methide; D009992:Osmium; D013879:Thioredoxins; D061105:Peroxiredoxin III; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D005978:Glutathione
keywords: Jurkat cancer cells; Osmocene; Osmocenyl-tamoxifen; ROS; Thioredoxin reductase