title: A new target for gold(I) compounds: glutathione-S-transferase inhibition by auranofin.
abstract: Nowadays, gold compounds occupy a relevant position constituting a promising class of experimental anticancer metallodrugs. Several research efforts have been devoted to the investigations of the pharmacological properties of gold(I) complexes bearing phosphine ligands, such as the antiarthritic drug auranofin, that has also been shown to produce anticancer effects in vitro. In spite of the numerous studies that appeared in the literature the biological mechanisms of action of auranofin and analogues are still controversial. Here, we report on the inhibition effects of glutathione S-transferase P1-1 (GST P1-1) exerted by auranofin. The compound was able to inhibit GST P1-1 with a calculated IC(50) of 32.9±0.5μM. Interestingly, the inhibition of GST P1-1 and its cysteine mutants by the gold(I) compound is essentially the same, suggesting that probably the cysteine residues are not so essential for enzyme inactivation in contrast to other reported inhibitors. High-resolution electrospray ionisation Fourier transform ion cyclotron mass spectrometry (ESI FT-ICR MS) studies allowed characterising the binding of the compound with GST enzymes at a molecular level, confirming that similar gold binding sites may be present in the wild-type protein and its Cys mutants.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica snc, Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D018501:Antirheumatic Agents / Q000737:chemistry*; D001310:Auranofin / Q000737:chemistry*; D001665:Binding Sites; D003545:Cysteine / Q000737:chemistry* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry; D004976:Ethacrynic Acid / Q000737:chemistry; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D001310:Auranofin; D051549:Glutathione S-Transferase pi; D003545:Cysteine; D004976:Ethacrynic Acid