Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias

• Published in: Molecular cancer therapeutics Vol. 5; no. 12; pp. 3113 - 3121
• Main Authors: Zeng, Zhihong, Samudio, Ismael J, Munsell, Mark, An, Jing, Huang, Ziwei, Estey, Elihu, Andreeff, Michael, Konopleva, Marina
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.12.2006
• Subjects: apoptosis; Chemokine CXCL12; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - metabolism; Chemokines, CXC - pharmacology; Chemotaxis - drug effects; chemotherapy; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; HL-60 Cells; Humans; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; MAP Kinase Signaling System; Peptides - pharmacology; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - biosynthesis; Proto-Oncogene Proteins c-akt - metabolism; Pyridines - pharmacology; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - biosynthesis; SDF-1/CXCR4; Stromal Cells - pathology; U937 Cells
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0228

The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1α (SDF-1α)–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-1α 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-1α– 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-1α–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-1α/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. [Mol Cancer Ther 2006;5(12):3113–21]