Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro

Br J Haematol. 2008 Dec;143(5):698-706. doi: 10.1111/j.1365-2141.2008.07418.x.

Abstract

The dual c-abl/Src kinase inhibitor, dasatinib, utilized to treat chronic myeloid leukaemia (CML) when used at clinically attainable sublethal concentrations, synergistically sensitized primary chronic lymphocytic leukaemia (CLL) lymphocytes to chlorambucil and fludarabine. In contrast, dasatinib alone demonstrated toxicity to CLL lymphocytes at concentrations that are generally not clinically attainable. Dasatinib resistance and poorer dasatinib-mediated sensitization to chlorambucil and fludarabine was associated with higher expression of c-abl protein levels. In contrast, chlorambucil and fludarabine resistance correlated with basal p53 protein levels. Moreover, Western blot analysis after in vitro treatment of primary CLL lymphocytes with dasatinib, chlorambucil and/or fludarabine, showed that dasatinib: (i) inhibited c-abl function (e.g. downregulation of c-abl protein levels and decreased the phosphorylation of a c-abl downstream target, Dok2), (ii) decreased chlorambucil/fludarabine induced accumulation of p53 protein levels, (iii) altered the response to chlorambucil/fludarabine induced DNA-damage as evidenced by an increase in chlorambucil/fludarabine-induced H2AX phosphorylation, and (iv) accentuated the c-abl downregulation induced by chlorambucil/fludarabine. Our results suggest that dasatinib in combination with chlorambucil or fludarabine may improve the therapy of CLL.

Publication types

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

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Blotting, Western / methods
  • Cell Survival
  • Chlorambucil / administration & dosage
  • Cytotoxicity Tests, Immunologic
  • DNA Mutational Analysis
  • Dasatinib
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Linear Models
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / therapeutic use*
  • Statistics, Nonparametric
  • Thiazoles / therapeutic use*
  • Tumor Suppressor Protein p53 / metabolism
  • Vidarabine / administration & dosage
  • Vidarabine / analogs & derivatives

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Chlorambucil
  • Proto-Oncogene Proteins c-abl
  • Vidarabine
  • fludarabine
  • Dasatinib