Induction of mitochondrial permeability transition by auranofin, a Gold(I)‐phosphine derivative

Abstract

1 Gold(I)-thiolate drugs are compounds that speci®cally interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. 2 Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the eects of aurano®n (S-triethylphosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-b-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. 3 Aurano®n, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the speci®c inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. 4 By interacting with the active site selenol group, aurano®n results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. 5 It is concluded that aurano®n, in the presence of calcium ions, is a highly ecient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase.

Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro

“…Very recently, it was reported that AF could also induce mitochondrial permeability transition (McKeage, 2002;Rigobello et al, 2002). In addition, we confirmed that cytochrome c is released from mitochondria into cytosol in the AF-induced apoptotic cells (data not shown).…”

Mechanisms of Cytotoxicity of Selected Organogold(III) Compounds

“…16 Rigobello et al have recently provided further experimental support for the linkages existing among the thioredoxin reductase/ thioredoxin system, the mitochondrial membrane permeability transition, and selective metal toxicity. 17 In collaboration with the group of Alberto Bindoli we have recently shown that various gold(I) and gold(III) compounds as well as other toxic agents behave as specific inhibitors of mitochondrial thioredoxin reductase; in particular, the effects of 1, 2, and 3 as inhibitors of thioredoxin reductase were evaluated. 18 The measured IC 50 values obtained for thioredoxin reductase inhibition, reported in Table 2, suggest that these compounds are indeed highly selective inhibitors of this crucial selenoenzyme although less potent than auranofin.…”

Mitochondrial Thioredoxin System

“…With regard to apoptosis, it was proposed that the mitochondrial thioredoxin/thioredoxin reductase system can play a role in redox regulation of the mitochondrial membrane permeability (46,47). In support of this suggestion, auranofin, a potent inhibitor of mitochondrial TrxR, was reported to induce MMP and loss of ⌬ in isolated mitochondria, two alterations that were completely inhibited by cyclosporin A, a specific inhibitor of mitochondrial permeability transition (48). Here we report the effect of transfection-mediated overexpression of TrxR2 or EGFP-tagged TrxR2 on mouse Neuro2A cell growth, mitochondrial transmembrane potential, ROS production, and viability, in response to a variety of prooxidant and non-oxidant inducers of apoptosis.…”