ZD6474 inhibits Src kinase leading to apoptosis of imatinib-resistant K562 cells

Leuk Res. 2009 Nov;33(11):1512-9. doi: 10.1016/j.leukres.2009.03.033. Epub 2009 Apr 25.

Abstract

ZD6474 is an orally available, small-molecule tyrosine kinase inhibitor. This study explores the effect of ZD6474 on imatinib-resistant K562 cell lines, which show markedly increased SRC family kinases (SFKs) activity. ZD6474 induces growth arrest and apoptosis of imatinib-resistant and parental K562 cells, as well as inhibition of Src activity and its downstream effectors, the anti-apoptotic Bcl-2 family. ZD6474 treatment also inhibits the activity of STAT3 and reactivation of its activity results in suppression of the anti-tumor effects of SFKs inhibitors. A single oral administration of ZD6474 produced dose-dependent inhibition of imatinib-resistant K562 cells xenograft tumors. These results suggest that clinical assessment of ZD6474 against imatinib-resistant CML is warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Base Sequence
  • Benzamides
  • Cell Cycle / drug effects
  • DNA Primers
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Imatinib Mesylate
  • Immunohistochemistry
  • K562 Cells
  • Piperazines / pharmacology*
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Quinazolines / pharmacology*
  • Transplantation, Heterologous
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Benzamides
  • DNA Primers
  • Piperazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • Imatinib Mesylate
  • src-Family Kinases
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine