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 determinedagainst 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.