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

Abstract

The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1A (SDF-1A) -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-1A 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-1A -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-1A -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-1A/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]

Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration

“…These findings are supported by the negative prognostic impact of high CXCR4 expression levels in patients with AML (Rombouts et al, 2004;Spoo et al, 2007). Consequently, targeting leukemic stem cells within the bone marrow by disruption of the CXCL12-CXCR4 interaction by small molecule inhibitors has been recently proposed (Zeng et al, 2006;Juarez et al, 2007).…”

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

“…22,23 Inhibition of CXCR4 has been able to overcome resistance to numerous drugs. 24,25 CXCR4 inhibitors that target the stromal interaction and release the leukemic cells from the microenvironment have both a mobilizing and cell-cycle activating effect upon leukemic cells and may sensitize AML for chemotherapeutic cell killing. 24,26 CXCR4 inhibitors induced mobilization of AML cells into circulation and enhanced antileukemic effects of chemotherapy, resulting in markedly reduced leukemia burden and prolonged survival.…”

“…24,25 CXCR4 inhibitors that target the stromal interaction and release the leukemic cells from the microenvironment have both a mobilizing and cell-cycle activating effect upon leukemic cells and may sensitize AML for chemotherapeutic cell killing. 24,26 CXCR4 inhibitors induced mobilization of AML cells into circulation and enhanced antileukemic effects of chemotherapy, resulting in markedly reduced leukemia burden and prolonged survival. 25 These effects resemble those of AML cell stimulation by G-CSF or GM-CSF, and synergy between the activities of hematopoietic growth factors (at least G-CSF) and CXCR4 inhibitors has been reported.…”

The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation

“…[13][14][15][16] CXCR4 blockage in AML cells, using the polypeptide RCP168, enhanced chemotherapy-induced apoptosis in vitro. 17 Most importantly, high CXCR4 expression level in leukemic cells was proved as a predictor of overall survival and relapsefree survival in patients with AML. 18,19 Although AML cells express variable levels of external CXCR4, high expression of internal CXCR4 is found.…”