Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4

Sergio Bernardini, Marzia Nuccetelli, Nélida I. Noguera, Lorenza Bellincampi, Paolo Lunghi, Antonio Bonati, Koren Mann, Wilson H. Miller, Giorgio Federici, Francesco Lo Coco

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Abstract

Arsenic trioxide (As2O3) is a highly effective agent in the treatment of acute promyelocytic leukemia (APL), whereas other hematopoietic tumors are less responsive to this agent and mechanisms underlying As2O3,-resistance are poorly understood. To better understand the complex network of GSH-related pathways in As2O3 sensitivity, we investigated the role of GSH and GSH-relevant enzymes in an APL cell line sensitive to s2O3 (NB4) and in a resistant subclone (AsR). Cell proliferation, viability, and apoptosis were investigated in NB4 cells before and after treatment with 1 μMA As2O3 and in AsR cells. In these experimental cell models, GSTP1-1, JNK1 and JNK2 proteins were analyzed by immunoblotting, and a kinase assay for JNK1 was performed. GSH levels as well as the activities of the enzymes glutathione peroxidase, glutathione transferase, γ-Glutamylcysteynilsinthetase and superoxide dismutase were measured. NB4 cells treated with As2O3 showed a high level of oxidative stress and an increase of GSH levels. GSTP1-1 polymerization and JNK1 activation were detectable after 24 h and were followed by an increase of the apoptotic rate starting at 72 h. Neither GSTP1-1 polymerization nor JNK activation was found in AsR cells that showed a very low apoptotic rate. Our results suggest that APL sensitivity to As2O3 might be, at least in part, mediated by the balance between association and dissociation of JNK from GSTP1-1, depending on the redox status of the cell. Further investigation is warranted to find a way to interfere with this balance, whenever it might represent a mechanism of drug resistance.

Original languageEnglish
Pages (from-to)681-687
Number of pages7
JournalAnnals of Hematology
Volume85
Issue number10
DOIs
Publication statusPublished - Oct 2006

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Keywords

  • Acute promyelocytic leukemia
  • Arsenic trioxide
  • Drug resistance
  • GSTP1-1
  • Oxidative stress

ASJC Scopus subject areas

  • Hematology

Cite this

Bernardini, S., Nuccetelli, M., Noguera, N. I., Bellincampi, L., Lunghi, P., Bonati, A., Mann, K., Miller, W. H., Federici, G., & Lo Coco, F. (2006). Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4. Annals of Hematology, 85(10), 681-687. https://doi.org/10.1007/s00277-006-0139-8