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 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.
Martinez-Lostao
Luis
L
Immunology Department, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Spain.
Briones
Javier
J
Forné
Ignasi
I
Martinez-Gallo
Monica
M
Ferrer
Beatriz
B
Sierra
Jordi
J
Rodriguez-Sanchez
Jose Luis
JL
Juarez
Candido
C
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D011799:Quinazolines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C116180:WHI P131; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D014740:Vidarabine; C024352:fludarabine