Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study.
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.
Magherini
Francesca
F
Department of Biochemical Sciences, University of Florence, Viale G. Morgagni, 50, 50134, Florence, Italy.
Modesti
Alessandra
A
Bini
Luca
L
Puglia
Michele
M
Landini
Ida
I
Nobili
Stefania
S
Mini
Enrico
E
Cinellu
Maria Agostina
MA
Gabbiani
Chiara
C
Messori
Luigi
L
D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006046:Gold / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013058:Mass Spectrometry; D040901:Proteomics
D003603:Cytotoxins; D001310:Auranofin; D006046:Gold