Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

  • Du Z
  • Zhang H
  • Meng X
 et al. 
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Abstract

BACKGROUND: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. METHODS: Proteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR. RESULTS: At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death. CONCLUSION: GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.

Author-supplied keywords

  • 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium
  • Adenosine Triphosphate/metabolism
  • Apoptosis/*drug effects/physiology
  • Boronic Acids/*pharmacology
  • Catalytic Domain/genetics
  • Cell Line, Tumor
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic/drug effec
  • Gene Expression Regulation, Neoplastic/drug effect
  • Glutamate-Cysteine Ligase/genetics/metabolism
  • Glutathione Synthase/genetics/metabolism
  • Glutathione/*metabolism
  • Humans
  • Intracellular Space/drug effects/metabolism
  • Oxidative Stress/*drug effects/physiology
  • Protease Inhibitors/pharmacology
  • Proteasome Endopeptidase Complex/antagonists & inh
  • Pyrazines/*pharmacology
  • Reactive Oxygen Species/metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrophotometry/methods
  • Thyroid Neoplasms/genetics/metabolism/pathology

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Authors

  • Z X Du

  • H Y Zhang

  • X Meng

  • Y Guan

  • H Q Wang

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