Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

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• 作者：Valentina G ; in ; Aristi Potamitou Fern ; es ; Maria Pia Rigobello ; Barbara Dani ; Francesca Sorrentino ; Francesco Tisato ; Mikael Bjö ; rnstedt ; Alberto Bindoli ; Alberto Sturaro ; Rocco Rella ; Cristina Mar
• 关键词：Thioredoxin reductase ; Phosphine metal complexes ; Apoptosis ; Drug resistance ; Cytotoxicity ; Oxidative stress
• 刊名：Biochemical Pharmacology
• 出版年：2010
• 出版时间：15 January 2010
• 年：2010
• 卷：79
• 期：2
• 页码：90-101
• 全文大小：561 K

文摘

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(PEt₃)]⁺ 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.