Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors that have been implicated in tumoral transformation, especially in hematological malignancies. Because of this, the JAK/STAT pathway is attractive as a therapeutic target in these tumors. In...

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Bibliographic Details
Published in:Leukemia & lymphoma 2005-03, Vol.46 (3), p.435-442
Main Authors: Martinez-Lostao, Luis, Briones, Javier, Forné, Ignasi, Martinez-Gallo, Monica, Ferrer, Beatriz, Sierra, Jordi, Rodriguez-Sanchez, Jose Luis, Juarez, Candido
Format: Article
Language:English
Subjects:
AG490
Aged
Aged, 80 and over
apoptosis
Apoptosis - drug effects
B-CLL
Cell Survival - drug effects
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - physiology
Electrophoretic Mobility Shift Assay
Female
Flow Cytometry
fludarabine
Humans
Interferon-gamma - pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Male
Middle Aged
Protein-Tyrosine Kinases - antagonists & inhibitors
Quinazolines - pharmacology
Signal Transduction - drug effects
Signal Transduction - physiology
STAT1
STAT1 Transcription Factor
Time Factors
Trans-Activators - antagonists & inhibitors
Trans-Activators - physiology
Tumor Cells, Cultured
Tyrphostins - pharmacology
Vidarabine - analogs & derivatives
Vidarabine - pharmacology
WHI-P131
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Summary:Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors that have been implicated in tumoral transformation, especially in hematological malignancies. Because of this, the JAK/STAT pathway is attractive as a therapeutic target in these tumors. In the present study, we analyzed the ability of fludarabine and two JAK kinase inhibitors, AG490 and WHI-P131, to block STAT1 activation and induce apoptosis on B-cell chronic lymphocytic leukemia (B-CLL) cells. All drugs were able to induce a high percentage of apoptosis on B-CLL cells from all patients studied. However, only AG490 and WHI-P131 were able to strongly suppress the STAT1 activation of B-CLL cells. In conclusion, our data show that JAK kinase inhibitors, such as AG490 and WHI-P131 are able to inhibit the STAT1 pathway on B-CLL cells and are strong inductors of apoptosis on these cells.
ISSN:1042-8194
1029-2403
DOI:10.1080/10428190400018398