Thioredoxin reductase, an emerging target for anticancer metallodrugs. Enzyme inhibition by cytotoxic gold(III) compounds studied with combined mass spectrometry and biochemical assays

Chiara Gabbiani, Guido Mastrobuoni, Francesca Sorrentino, Barbara Dani, Maria Pia Rigobello, Alberto Bindoli, Maria Agostina Cinellu, Giuseppe Pieraccini, Luigi Messori, Angela Casini*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

72 Citations (Scopus)

Abstract

The seleno-enzyme thioredoxin reductase (TrxR) is a putative target for cytotoxic gold complexes. We investigated the mechanism of TrxR inhibition by a group of structurally diverse gold(m) compounds; the antiarthritic gold(I) drugs auranofin and aurothiomalate were also studied for comparison purposes. The tested compounds - either gold(III) or gold(I) - were found to produce potent enzyme inhibition only after pre-reduction of the enzyme with NADPH, indicating that TrxR inhibition is the result of protein structure modifications occurring upon cofactor binding. MALDI-ToF MS experiments on the intact enzyme provided evidence for extensive enzyme metallation, while experiments on trypsinized gold(III)-protein adducts identified a specific protein fragment - namely (236)IGEHMEEHGIK(246) - bearing an attached gold(I) ion. Independent mechanistic information on the system was derived from BIAM assays capable of monitoring selective metal binding to cysteine and/or selenocysteine residues. While the effects produced by auranofin could be essentially ascribed to gold(I) coordination to the active site selenol, the effects caused by the various gold(III) compounds were better interpreted in terms of oxidative protein damage.

Original languageEnglish
Pages (from-to)50-54
Number of pages5
JournalMedChemComm
Volume2
Issue number1
DOIs
Publication statusPublished - Jan-2011
Externally publishedYes

Keywords

  • SOLUTION CHEMISTRY
  • GLUTATHIONE-REDUCTASE
  • MOLECULAR-MECHANISM
  • ANTITUMOR AGENTS
  • CANCER-THERAPY
  • GOLD COMPOUNDS
  • SERUM-ALBUMIN
  • COMPLEXES
  • LIGANDS
  • BINDING

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