title: Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase.
abstract: The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH (nicotinamide adenine dinucleotide phosphate), plays a central role in regulating cellular redox homeostasis and signaling pathways. TrxR, overexpressed in many tumor cells and contributing to drug resistance, has emerged as a new target for anticancer drugs. Gold complexes have been validated as potent TrxR inhibitors in vitro in the nanomolar range. In order to obtain potent and selective TrxR inhibitors, we have synthesized a series of linear, 'auranofin-like' gold(I) complexes all containing the [Au(PEt(3))](+) synthon and the ligands: Cl(-), Br(-), cyanate, thiocyanate, ethylxanthate, diethyldithiocarbamate and thiourea. Phosphine gold(I) complexes efficiently inhibited cytosolic and mitochondrial TrxR at concentrations that did not affect the two related oxidoreductases glutathione reductase (GR) and glutathione peroxidase (GPx). The inhibitory effect of the redox proteins was also observed intracellularly in cancer cells pretreated with gold(I) complexes. Gold(I) compounds were found to induce antiproliferative effects towards several human cancer cells some of which endowed with cisplatin or multidrug resistance. In addition, they were able to activate caspase-3 and induce apoptosis observed as nucleosome formation and sub-G1 cell accumulation. The complexes with thiocyanate and xanthate ligands were particularly effective in inhibiting thioredoxin reductase and inducing apoptosis. Pharmacodynamic studies in human ovarian cancer cells allowed for the correlation of intracellular drug accumulation with TrxR inhibition that leads to the induction of apoptosis via the mitochondrial pathway.
authors: Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, 35121 Padova, Italy.
authors: Valentina
authors: V
authors: Gandin
authors: Aristi Potamitou
authors: AP
authors: Fernandes
authors: Maria Pia
authors: MP
authors: Rigobello
authors: Barbara
authors: B
authors: Dani
authors: Francesca
authors: F
authors: Sorrentino
authors: Francesco
authors: F
authors: Tisato
authors: Mikael
authors: M
authors: Björnstedt
authors: Alberto
authors: A
authors: Bindoli
authors: Alberto
authors: A
authors: Sturaro
authors: Rocco
authors: R
authors: Rella
authors: Cristina
authors: C
authors: Marzano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006046:Gold / Q000737:chemistry*; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D010720:Phosphines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D010720:Phosphines; D017382:Reactive Oxygen Species; D006046:Gold; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase