Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias.
The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1alpha (SDF-1alpha)-producing bone marrow microenvironment. Using peptide-based CXCR4 inhibitors derived from the chemokine viral macrophage inflammatory protein II, we tested the hypothesis that the inhibition of CXCR4 increases sensitivity to chemotherapy by interfering with stromal/leukemia cell interactions. First, leukemic cells expressing varying amounts of surface CXCR4 were examined for their chemotactic response to SDF-1alpha or stromal cells, alone or in the presence of different CXCR4 inhibitors. Results showed that the polypeptide RCP168 had the strongest antagonistic effect on the SDF-1alpha- or stromal cell-induced chemotaxis of leukemic cells. Furthermore, RCP168 blocked the binding of anti-CXCR4 monoclonal antibody 12G5 to surface CXCR4 in a concentration-dependent manner and inhibited SDF-1alpha-induced AKT and extracellular signal-regulated kinase phosphorylation. Finally, RCP168 significantly enhanced chemotherapy-induced apoptosis in stroma-cocultured Jurkat, primary chronic lymphocytic leukemia, and in a subset of acute myelogenous leukemia cells harboring Flt3 mutation. Equivalent results were obtained with the small-molecule CXCR4 inhibitor AMD3465. Our data therefore suggest that the SDF-1alpha/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Disruption of these interactions by the peptide CXCR4 inhibitor RCP168 represents a novel strategy for targeting leukemic cells within the bone marrow microenvironment.
Zeng
Zhihong
Z
Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, Unit 448, 1515 Holcombe Boulevard, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Samudio
Ismael J
IJ
Munsell
Mark
M
An
Jing
J
Huang
Ziwei
Z
Estey
Elihu
E
Andreeff
Michael
M
Konopleva
Marina
M
D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017154:Stromal Cells / Q000473:pathology; D020298:U937 Cells
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D010455:Peptides; D011725:Pyridines; D019718:Receptors, CXCR4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases