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Article Dans Une Revue Journal of Inorganic Biochemistry Année : 2016

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

Résumé

To complete our study of the iron, ruthenium and osmium metallocene triad derived from hydroxytamoxifen, we report here the synthesis and study of 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 derivatives, 1-QM and 2-QM. Studies carried out in vitro on purified thioredoxin reductase (TrxR) show that the characteristic inhibition of TrxR is observed with 1 and 2 only after their enzymatic oxidation by the H 2 O 2 /HRP system. The observed inhibition is very similar for the two complexes (IC 50 = 2.4 and 1.2 µM for 1 and 2 after treatment by HRP/H 2 O 2) but different from that obtained with the corresponding quinone methides (IC 50 = 5.4 and 3.6 µM for 1-QM and 2-QM). The UV spectra of 1 or 2 incubated in the presence of HRP/H 2 O 2 show that the species generated by enzymatic oxidation is not a quinone methide but more probably its corresponding cation. On Jurkat cells, complexes 1 and 2 behave differently. Indeed, while 2 shows high toxicity (IC 50 = 7.4 µM), that of 1 is much more modest (IC 50 = 42 µM). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition for incubation in the presence of 15 µM) while that induced by 1 is much weaker (about 30% inhibition for incubation in the presence of 50 µM). This strong inhibition of TrxR activity induced by 2 leads to accumulation of thioredoxin and peroxiredoxin 3 in oxidized form as well as a significant decrease of the mitochondrial membrane potential (MMP). These results show that the cytotoxicity of the osmocifens depends on their oxidation within the cell and that inhibition of thioredoxin reductase is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.
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Dates et versions

hal-01313082 , version 1 (09-05-2016)

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Valeria Scalcon, Siden Top, Hui Zhi Shirley Lee, Anna Citta, Alessandra Folda, et al.. Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells. Journal of Inorganic Biochemistry, 2016, 160, pp.296-304. ⟨10.1016/j.jinorgbio.2016.04.005⟩. ⟨hal-01313082⟩
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