Inhibition of CXCR4 with Novel Peptide May Help fight CLL, Other Blood Cancers

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Mol Cancer Ther. 2006 Dec;5(12):3113-21.

Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-

mediated chemoresistance in chronic and acute leukemias.

Zeng Z, Samudio IJ, Munsell M, An J, Huang Z, Estey E, Andreeff M,

Konopleva M.

Department of Blood and Marrow Transplantation, Section of Molecular

Hematology and Therapy, Unit 448, 1515 Holcombe Boulevard, The

University of Texas M.D. Cancer Center, Houston, TX 77030.

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. [Mol Cancer

Ther 2006;5(12):3113-21].

PMID: 17172414 [PubMed - in process]

* These are small, secreted protein signals that signal leukocytes

to move in a specific direction.