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 As2O3 (NB4) and in a resistant subclone (AsR). Cell proliferation, viability, and apoptosis were investigated in NB4 cells before and after treatment with 1 muM 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, gamma-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.
Bernardini, S., Nuccetelli, M., Noguera, N.I., Bellincampi, L., Lunghi, P., Bonati, A., et al. (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 [10.1007/s00277-006-0139-8].
|Tipologia:||Articolo su rivista|
|Citazione:||Bernardini, S., Nuccetelli, M., Noguera, N.I., Bellincampi, L., Lunghi, P., Bonati, A., et al. (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 [10.1007/s00277-006-0139-8].|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1007/s00277-006-0139-8|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2006|
|Titolo:||Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4|
|Autori:||Bernardini, S; Nuccetelli, M; Noguera, NI; Bellincampi, L; Lunghi, P; Bonati, A; Mann, K; Miller Jr, Wh; Federici, G; Lo Coco, F|
|Appare nelle tipologie:||01 - Articolo su rivista|