Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study |
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Authors: | Francesca Magherini Alessandra Modesti Luca Bini Michele Puglia Ida Landini Stefania Nobili Enrico Mini Maria Agostina Cinellu Chiara Gabbiani Luigi Messori |
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Institution: | (1) Department of Biochemical Sciences, University of Florence, Viale G. Morgagni, 50, 50134 Florence, Italy;(2) Department of Molecular Biology, University of Siena, Siena, Italy;(3) Department of Pharmacology, University of Florence, viale Pieraccini 6, 50139 Florence, Italy;(4) Department of Chemistry, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;(5) Department of Chemistry, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy |
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Abstract: | We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human
tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper
insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin,
a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined
against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin
and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused
relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored
spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments.
Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton
and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles
in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with
caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly
related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds
trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis. |
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