Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib

Leuk Lymphoma. 2009 Oct;50(10):1676-86. doi: 10.1080/10428190903150847.

Abstract

Despite Imatinib's remarkable success in chronic myelogenous leukemia treatment, monotherapy frequently causes resistance, underlining the rationale for combination chemotherapy. A potential approach would be interrupting the SDF-1/CXCR4 axis using the selective CXCR4 antagonist Plerixafor (previously AMD3100), as this axis has been reported to provide survival-enhancing effects to myeloid progenitor cells. By efficient CXCR4 blocking in the CXCR4(+)/BCR-ABL(+) cell line BV-173, plerixafor (1-100 muM) significantly inhibits SDF-1alpha-mediated chemotaxis and cell migration toward the murine stroma cell line FBMD-1. Furthermore, plerixafor also significantly (10-100 muM) increased the detachment rate of SDF-1-mediated/VCAM-1-associated cell adherence under shear stress. Using a stroma-dependent coculture assay, plerixafor sensitized BCR-ABL(+) cells toward tyrosine kinase inhibitor therapy. Because the level of cell killing nearly reached that of samples cultured without stroma, a cell-cell interaction disruption seems to improve the efficacy of BCR-ABL-targeting drugs. In addition, we could show that exposure of BCR-ABL(+) cells to Imatinib or Nilotinib induced an increase in surface CXCR4 expression. Our data suggest that for BCR-ABL(+) leukemia, the selective blocking of the SDF-1/CXCR4 axis by plerixafor is a potential mechanism to overcome the protective effect of the bone marrow environment, thereby increasing the therapeutic potency of anti-BCR-ABL drugs and the therapeutic window.

MeSH terms

  • Animals
  • Benzamides
  • Cell Adhesion / drug effects
  • Cell Line / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / enzymology
  • Cell Line, Tumor / pathology
  • Chemokine CXCL12 / antagonists & inhibitors*
  • Coculture Techniques
  • Drug Resistance, Neoplasm / drug effects
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / biosynthesis
  • Receptors, CXCR4 / chemistry
  • Receptors, CXCR4 / genetics
  • Stromal Cells / cytology

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Benzamides
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Heterocyclic Compounds
  • Neoplasm Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, CXCR4
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • plerixafor