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
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 (pre...
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Published in | Leukemia & lymphoma Vol. 50; no. 10; pp. 1676 - 1686 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Informa UK Ltd
01.01.2009
Taylor & Francis |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1042-8194 1029-2403 |
DOI: | 10.1080/10428190903150847 |