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 language | English |
|---|---|
| Pages (from-to) | 681-687 |
| Number of pages | 7 |
| Journal | Annals of Hematology |
| Volume | 85 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 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
Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4. / Bernardini, Sergio; Nuccetelli, Marzia; Noguera, Nélida I.; Bellincampi, Lorenza; Lunghi, Paolo; Bonati, Antonio; Mann, Koren; Miller, Wilson H.; Federici, Giorgio; Lo Coco, Francesco.
In: Annals of Hematology, Vol. 85, No. 10, 10.2006, p. 681-687.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4
AU - Bernardini, Sergio
AU - Nuccetelli, Marzia
AU - Noguera, Nélida I.
AU - Bellincampi, Lorenza
AU - Lunghi, Paolo
AU - Bonati, Antonio
AU - Mann, Koren
AU - Miller, Wilson H.
AU - Federici, Giorgio
AU - Lo Coco, Francesco
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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.
KW - Acute promyelocytic leukemia
KW - Arsenic trioxide
KW - Drug resistance
KW - GSTP1-1
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=33747477512&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747477512&partnerID=8YFLogxK
U2 - 10.1007/s00277-006-0139-8
DO - 10.1007/s00277-006-0139-8
M3 - Article
VL - 85
SP - 681
EP - 687
JO - Annals of Hematology
JF - Annals of Hematology
SN - 0939-5555
IS - 10
ER -