Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro.
Stromal cell-derived factor-1 (SDF-1) is a key regulator of the behavior of normal and leukemic precursor-B (pre-B) cells. It is possible that inhibiting SDF-1-driven processes in pre-B acute lymphoblastic leukemia (ALL) may have therapeutic implications. In this study, we examined the ability of SDF-1 inhibitors to modulate pre-B ALL cell responses to SDF-1, including chemotaxis, migration into bone marrow stroma, and stroma-supported survival and proliferation on human bone marrow stromal layers. The polyphemusin II-derived inhibitors, T140, TC140012, and T134, and the bicyclam AMD3100, effectively inhibited binding of the anti-CXCR4 monoclonal antibody 12G5 on the pre-B ALL cell line NALM6, with IC(50) values of 0.9, 0.9, 0.9, and 1.9 nM, respectively. Similar results were obtained with ALL samples. T140 (0.1 micro M) and AMD3100 (1 micro M) completely blocked SDF-1-induced chemotaxis and attenuated the migration of pre-B ALL cells into bone marrow stromal layers. AMD3100 and TC140012 at a concentration of 50 micro M significantly inhibited stroma-dependent proliferation of six and four of the eight cases tested, respectively, without reducing the cell viability. In addition, AMD3100 and TC140012 enhanced the cytotoxic and antiproliferative effects of the cytotoxic agents vincristine and dexamethasone. The ability of SDF-1 inhibitors to modulate these biologically important functions of leukemic cells warrants further investigation.
Juarez
J
J
Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Australia.
Bradstock
K F
KF
Gottlieb
D J
DJ
Bendall
L J
LJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001596:Benzylamines; D002455:Cell Division / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D000080027:Cyclams; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000166:cytology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D019718:Receptors, CXCR4; C116978:T134 peptide; D014750:Vincristine; D003907:Dexamethasone; C116977:T140 peptide; C088327:plerixafor