Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells

Marzano, Christine; Gandin, Valentina; Folda, Alessandra; Scutari, Guido; Bindoli, Alberto

doi:10.1016/j.freeradbiomed.2006.12.021

Cited by 371 publications

(314 citation statements)

References 47 publications

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“…However, very recently, additional in vitro studies indicated that auranofin is able to overcome cisplatin resistance in human 4 ovarian cancer cells [9], confirming the earlier assumption that a mechanism of action different from the recognized DNA damage induced by cisplatin could underlie the cytotoxic activity of phosphine Au(I) drugs. In particular, it was found that auranofin, acting as a potent inhibitor of thioredoxin reductase, causes an alteration of the redox state of the cell leading to an increased production of hydrogen peroxide and oxidation of the components of the thioredoxin (Trx) system, therefore creating the conditions for enhanced apoptosis [9].…”

Section: Introductionsupporting

confidence: 60%

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

Gandin

Fernandes

Dani

et al. 2010

Biochemical Pharmacology

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222

186

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The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH (Nicotinamide adenine dinucleotide 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 correlatation of intracellular drug accumulation with TrxR inhibition that leads to the induction of apoptosis via the mitochondrial pathway.

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Section: Introductionsupporting

confidence: 60%

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

Gandin

Fernandes

Dani

et al. 2010

Biochemical Pharmacology

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222

186

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“…The behavior of Auoxo6 is compared with that of auranofin, a gold(I) antiarthritic drug, endowed with significant cytotoxic properties in vitro (but not in vivo) [7]. Auranofin was chosen as a control compound since it is a typical gold(I) drug in clinical use and a lot is known about its biochemical effects at the cellular level [8,9]. The chemical structures of Auoxo6 and auranofin are shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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“…IC 50 values represent the drug concentrations that reduced the mean absorbance at 570 nm to 50% of those in the untreated control wells. The condensation reaction, carried out in DMF solution was monitored by 31 P NMR spectroscopy showing that, at room temperature, a complex mixture of products is formed. At 70°C, in a few days, it converts quantitatively into the trinuclear species 1 characterized by two AB multiplets, having relative intensities of 2:1, at δ −27.01 ( 1 J PPt = 3126 Hz), 28.31 (3234 Hz) at δ −27.14 ( 1 J PPt = 3126 Hz), 28.58 (3234 Hz, with 2 J PP =24.8 Hz) ppm, respectively.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

“…The presence of two sets of signals for the nucleoside is in line with the existence of two conformers resulting in the relative orientation, syn and anti, of the ribose groups with respect to the pyrimidinic ring. The reaction of the hydroxo complex with the bulkier PPh 3 ligands, was carried out in DMF or CH 2 Cl 2 /MeOH solution and monitored by 31 P NMR spectroscopy. In both cases, complex 4 was formed in high yield (N80%).…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

“…Although cisplatin resistance is multifactorial, the main molecular mechanisms involved in Pt resistance of C13* and A431/Pt have been identified. In particular, in C13* cells' resistance is correlated to reduced cellular drug uptake, high cellular glutathione and thioredoxin reductase levels and enhanced repair of DNA damage [30,31]. In A431/Pt cells, resistance is due to a defect in drug uptake and to decreased levels of proteins involved in DNA mismatch repair (MSH2), which causes an increased tolerance to cisplatin-induced DNA damage [32].…”

Section: Cytotoxicity Testsmentioning

confidence: 99%

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Synthesis, characterization and cytotoxic properties of platinum(II) complexes containing the nucleosides adenosine and cytidine

Montagner

Gandin

Marzano

et al. 2011

Journal of Inorganic Biochemistry

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a b s t r a c t a r t i c l e i n f o. When the condensation reaction is carried out in solution of nitriles (RCN, R = Me, Ph) the amidine derivatives cis-[(PPh 3 ) 2 PtNH=C(R){cyt(− 2H)}]NO 3 (R = Me, 5a; R = Ph, 5b) and cis-[(PPh 3 ) 2 PtNH= C(R){ado(− 2H)}]NO 3 (R = Me, 6a: R = Ph, 6b) are quantitatively formed. The coordination mode of these nucleosides, characterized in solution by multinuclear NMR spectroscopy and mass spectrometry, is similar to that previously observed for the nucleobases 1-methylcytosine (1-MeCy) and 9-methyladenine (9-MeAd). The cytotoxic properties of the new complexes, and those of the nucleobase analogs, cis-[(PPh 3 ) 2 PtNH=C(R) {1-MeCy(− 2H)}]NO 3 (R = Me, 7a: R = Ph, 7b), cis-[(PPh 3 ) 2 PtNH=C(R){9-MeAd(− 2H)}]NO 3 (R = Me, 8a: R = Ph, 8b) have been investigated in a wide panel of human cancer cells. Interestingly, whereas the Pt(II) nucleoside complexes (1-4) did not show appreciable cytotoxicity, the corresponding amidine derivatives (7a, 7b, 8a, 8b, 5b, and 6b) exhibited a significant in vitro antitumor activity.

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Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells

Cited by 371 publications

References 47 publications

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

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

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

Synthesis, characterization and cytotoxic properties of platinum(II) complexes containing the nucleosides adenosine and cytidine

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