Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

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.

Proteomic analysis of A2780/S ovarian cancer cell response to the cytotoxic organogold(III) compound Aubipyc

“…Concerning the A2780/S, the results pointed out that the mode of action of Auoxo6 is strictly related to that of auranofin. Both gold compounds trigger caspase 3 activation and apoptosis and the affected proteins are involved in cell redox homeostasis and stress response [28]. Conversely, in the A2780/R cell line, Auranofin affected the expression of proteasome apparatus proteins whereas Auoxo6 modified the expression of proteins related to mRNA trafficking and stability [29].…”

New Insights into the Molecular Mechanisms of Selected Anticancer Metal Compounds through Bioinformatic Analysis of Proteomic Data

“…Among this group, we found another intermediate node, an actin-related protein involved in cytoskeleton organization [28] (ACTR6-Q9GZN1). The protein SMN2 (Q16637) is a node between two input proteins involved in splicing: the Heterogeneous nuclear ribonucleoprotein H (P31943) [2], and the Serine-threonine kinase receptor-associated protein (Q9Y3F4) [1]. The SMN2 protein plays an essential role in spliceosomal assembly, and is required for pre-mRNA splicing [29].…”

“…Proteomic results have the potential to provide new insight into the molecular mechanisms of this group of molecules at the cellular level [2]. More than 99% of currently approved clinical drugs are organic compounds.…”

“…cell line (A2780/S), after treatment with four different cytotoxic gold compounds, namely: Auranofin [2], Auoxo6 [2], AuL12 [1] and Au2Phen [1]. In a very recent paper, we have used for the first time, 2D-DIGE to investigate the mode of action of two anticancer ruthenium compounds, namely NAMI-A and RAPTA-T in A2780/S human cancer cells [18].…”

Proteomic and Metallomic Strategies for Understanding the Mode of Action of Anticancer Metallodrugs

“…Very recently, we have exploited a classical proteomic approach to gain a deeper insight into the mechanism of two cytotoxic gold compounds, namely Auoxo6, a binuclear gold(III) complex showing a very favourable cytotoxic profile, and auranofin, a clinically established gold(I) antiarthritic drug, causing relevant tumor cell growth inhibition in vitro [56]. First, the 72h cytotoxicity profiles of Auoxo6 and auranofin were carefully recorded against A2780 human ovarian carcinoma cells, either sensitive or resistant to cisplatin.…”