Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 160, Issue -, Pages 296-304Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2016.04.005
Keywords
Osmocene; Osmocenyl-tamoxifen; Thioredoxin reductase; ROS; Jurkat cancer cells
Funding
- Ministero dell'Istruzione, Universita e Ricerca (MIUR) Italy [PRIN 20107Z8XBW]
- University of Padova (Italy) [CPDA130272]
- COST Actions [CM1105, CM1106]
- NTU-ParisTech joint PhD Programme
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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 1.2 mu M respectively. However, this inhibition is larger than that obtained with the corresponding quinone methides (IC50 = 5.4 M for 1-QM and 3.6 mu M 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 = 7.4 mu M), while 1 is less effective (IC50 = 42 mu M). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition with 15 mu M) while the inhibition induced by 1 is much weaker (about 30% inhibition with 50 M). 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. (C) 2016 Elsevier Inc. All rights reserved.
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