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

Free Radic Biol Med. 2007 Mar 15;42(6):872-81. doi: 10.1016/j.freeradbiomed.2006.12.021. Epub 2006 Dec 22.

Abstract

Cisplatin is an effective antitumor agent for the treatment of several carcinomas. However, the development of resistance to cisplatin represents a serious clinical problem. The effects of auranofin, a gold(I) compound clinically used as an antirheumatic agent, on cisplatin-sensitive (2008) and-resistant (C13*) cancer cells were studied. Auranofin is more effective than cisplatin in decreasing cell viability and its action is particularly marked in C13* cells, indicating that no cross-resistance occurs. Furthermore, auranofin is able to permeate C13* cells more efficiently than 2008 cells. Treatment with auranofin determines a consistent release of cytochrome c in both cell lines, while cisplatin is effective only in sensitive cells. Both auranofin and cisplatin induce apoptosis in 2008 cells, while in C13* cells only auranofin is effective. Apoptosis is accompanied by an increased production of hydrogen peroxide that, however, is inhibited by N-acetyl-L-cysteine. In resistant cells, H(2)O(2) production is counteracted by a large overexpression of thioredoxin reductase that constitutes the preferred target of the inhibitory action of auranofin. This specific effect of auranofin might rationalize its ability in overcoming cisplatin resistance in human ovarian cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antirheumatic Agents / pharmacology
  • Apoptosis*
  • Auranofin / pharmacology*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Mitochondria / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Antirheumatic Agents
  • Auranofin
  • Cytochromes c
  • Thioredoxin-Disulfide Reductase
  • Cisplatin
  • Acetylcysteine