The CXCR4/CXCL12 axis plays a role in
cancer metastases,
stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in
stem cell mobilization prior to
autologous transplantation in
hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer
therapy are not available. To develop new CXCR4 antagonists a rational,
ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the
vMIP-II inhibitory
chemokine formed the core of nineteen
cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and
calcium efflux.
Peptides R, S and I were chosen for evaluation in in vivo models of lung
metastases (B16-CXCR4 and KTM2 murine
osteosarcoma cells) and growth of a renal cells xenograft.
Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced
calcium efflux. The four
peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human
melanoma cells. Intraperitoneal treatment with
peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung
metastases in C57/BL mice. KTM2
osteosarcoma lung
metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three
peptides significantly inhibited subcutaneous growth of SN12C-EGFP
renal cancer cells. A novel class of CXCR4 inhibitory
peptides was discovered. Three
peptides, R, I and S inhibited lung
metastases and primary
tumor growth and will be evaluated as
anticancer agents.