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

• Published in: Leukemia & lymphoma Vol. 50; no. 10; pp. 1676 - 1686
• Main Authors: Dillmann, Falk, Veldwijk, Marlon R., Laufs, Stephanie, Sperandio, Markus, Calandra, Gary, Wenz, Frederik, Zeller, W. Jens, Fruehauf, Stefan
• Format: Journal Article
• Language: English
• Published: United States Informa UK Ltd 01.01.2009; Taylor & Francis
• Subjects: Animals; Benzamides; Benzylamines; 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; CML; Coculture Techniques; CXCR4; Cyclams; Drug Resistance, Neoplasm - drug effects; Fusion Proteins, bcr-abl - antagonists & inhibitors; Heterocyclic Compounds - pharmacology; Heterocyclic Compounds - therapeutic use; Humans; imatinib; 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; nilotinib; Piperazines - pharmacology; plerixafor; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - biosynthesis; Receptors, CXCR4 - chemistry; Receptors, CXCR4 - genetics; SDF-1; Stromal Cells - cytology
• ISSN: 1042-8194; 1029-2403
• DOI: 10.1080/10428190903150847

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 μM) significantly inhibits SDF-1α-mediated chemotaxis and cell migration toward the murine stroma cell line FBMD-1. Furthermore, plerixafor also significantly (10-100 μM) 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.