Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene

Jpn J Cancer Res. 1997 Feb;88(2):108-10. doi: 10.1111/j.1349-7006.1997.tb00354.x.

Abstract

Overexpression of the human gamma-glutamylcysteine (gamma-GCS) gene resulted in cisplatin resistance with an increased glutathione (GSH) content, increased ATP-dependent glutathione S-conjugate export pump (GS-X pump) activity and decreased platinum accumulation in human lung cancer cells transfected with a gamma-GCS cDNA expression vector, as we previously reported. In this study, we examined the effects of buthionine sulfoximine (BSO), a specific inhibitor of gamma-GCS, to determine whether GSH depletion alters cisplatin resistance in a gamma-GCS-transfected cell line, SBC-3/GCS. In the presence of 10 microM BSO for 4 days, SBC-3/GCS still showed resistance to cisplatin, although it was partially reversed. Under these conditions, GS-X pump activity remained up-regulated in spite of low GSH content, and the platinum content was decreased. These data suggest that the GS-X pump itself influences cisplatin resistance, as well as cellular GSH content.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacyltransferases*
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antineoplastic Agents / metabolism*
  • Buthionine Sulfoximine / pharmacology*
  • Carrier Proteins / drug effects*
  • Carrier Proteins / metabolism
  • Cisplatin / metabolism*
  • Drug Resistance, Neoplasm
  • Glutathione / drug effects
  • Glutathione / metabolism*
  • Humans
  • Membrane Transport Proteins
  • Peptidyl Transferases / antagonists & inhibitors
  • Peptidyl Transferases / genetics*
  • Peptidyl Transferases / metabolism
  • RNA Processing, Post-Transcriptional
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Carrier Proteins
  • Membrane Transport Proteins
  • glutathione transporter
  • Buthionine Sulfoximine
  • Aminoacyltransferases
  • Peptidyl Transferases
  • glutathione gamma-glutamylcysteinyltransferase
  • Glutathione
  • Cisplatin