Anti-leukemic activity of dasatinib in both p53(wild-type) and p53(mutated) B malignant cells

Invest New Drugs. 2012 Feb;30(1):417-22. doi: 10.1007/s10637-010-9564-6. Epub 2010 Oct 16.

Abstract

The multi-kinase inhibitor dasatinib induced a variable but significant decrease of viability in both p53(wild-type) (EHEB, JVM-2, JVM-3) and p53(mutated) (MEC-1, MEC-2, BJAB) prolymphocytic B leukemic cells, due to a combination of cell cycle block in G1 and apoptosis. Antibody phospho-kinase array analysis revealed that dasatinib inhibited the phosphorylation of various kinases, including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors, in both p53(wild-type) and p53(mutated) cells. Therefore, dasatinib might offer a novel therapeutic strategy not only for p53(wild-type), but also for p53(mutated) B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dasatinib
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Granulocyte Precursor Cells / drug effects*
  • Granulocyte Precursor Cells / metabolism
  • Granulocyte Precursor Cells / pathology
  • Humans
  • Leukemia, Prolymphocytic, B-Cell / genetics
  • Leukemia, Prolymphocytic, B-Cell / metabolism*
  • Leukemia, Prolymphocytic, B-Cell / pathology
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • Thiazoles / pharmacology*
  • Time Factors
  • Tumor Suppressor Protein p53 / genetics*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TP53 protein, human
  • Thiazoles
  • Tumor Suppressor Protein p53
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Dasatinib