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

Leuk Lymphoma. 2005 Mar;46(3):435-42. doi: 10.1080/10428190400018398.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apoptosis / drug effects*
  • Cell Survival / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / physiology*
  • Electrophoretic Mobility Shift Assay
  • Female
  • Flow Cytometry
  • 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*
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Time Factors
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / physiology*
  • Tumor Cells, Cultured
  • Tyrphostins / pharmacology*
  • Vidarabine / analogs & derivatives*
  • Vidarabine / pharmacology*

Substances

  • DNA-Binding Proteins
  • Quinazolines
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Tyrphostins
  • WHI P131
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • Vidarabine
  • fludarabine