Abstract
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.
Highlights
Chemokines are a large family of 8 to 12 kDa peptides that serve as chemoattractants for cellular activation, differentiation and trafficking
B16-CXCR4 murine melanoma cell line were transfected with pYF1-fusin plasmid containing CXCR4 gene SN12C human renal cancer cells were transfected with pEGFP-1 (BD biosciences Clontech)
Previous NMR studies on the vMIP-II N-terminal tail showed that a structured motif encompassing tryptophan 5 to proline 8 (W5-P8) preserved its conformation in the intact protein, making this motif a promising candidate scaffold to design short CXCR4-ligand peptides
Summary
Chemokines are a large family of 8 to 12 kDa peptides that serve as chemoattractants for cellular activation, differentiation and trafficking. The chemokine CXCL12 (stromal cell-derived factor-1a) binds to the CXCR4 and CXCR7 receptors, initiating divergent signaling pathways that result in chemotaxis, cell survival and/or proliferation, increased intracellular calcium and transcription of genes critical for cell inflammation and cancer metastases [4,5]. CXCR4 receptor activation is mediated by coupling to an intracellular heterotrimeric G-protein associated with the inner surface of the plasma membrane [4,5]. It was initially thought that CXCR4 only transduces through an intracellular heterotrimeric G-protein subunit Gai [4], recent evidence suggests CXCR4 involves Gaq, Gao, and Gas and activates different downstream pathways. While CXCR4 activity is primarily G-protein mediated, the transduction pathway originating from the CXCR7 receptor seems to involve the b-arrestin pathway and is G-protein independent [9,10]
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