Suppression of vascular endothelial growth factor (VEGF) expression by targeting the Bcr-Abl oncogene and protein tyrosine kinase activity in Bcr-Abl-positive leukaemia cells

J Int Med Res. 2009 Mar-Apr;37(2):426-37. doi: 10.1177/147323000903700218.

Abstract

Studies have shown that vascular endothelial growth factor (VEGF), a major and potent inducer of angiogenesis, is directly triggered by the disease-related oncogene Bcr-Abl in Bcr-Abl-positive cells. In this study, inhibition of Bcr-Abl tyrosine kinase activity by imatinib significantly decreased VEGF expression in Bcr-Abl-positive K562 cells in vitro. Imatinib treatment in vivo of nude mice xenografted with K562 cells resulted in a significant reduction in tumour size and microvessel density compared with untreated tumours. In addition, interfering with Bcr-Abl oncogene expression with small interfering RNAs (siRNAs) not only induced a specific reduction of Bcr-Abl mRNA and protein expression, but also efficiently inhibited the expression of VEGF in K562 cells. Combined treatment with imatinib and Bcr-Abl-targeting siRNAs resulted in an enhanced effect on VEGF suppression in K562 cells. The combined application of Bcr-Abl-targeting siRNAs and imatinib may provide a potent novel therapeutic approach for chronic myeloid leukaemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Line, Tumor
  • Fusion Proteins, bcr-abl / genetics*
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Mice, Nude
  • Microvessels / drug effects
  • Microvessels / pathology
  • Piperazines / pharmacology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Benzamides
  • Piperazines
  • Pyrimidines
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl