Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases

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 sui...

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Main Authors:	Portella, Luigi, Vitale, Rosamaria, De Luca, Stefania, D’Alterio, Crescenzo, Ieranò, Caterina, Napolitano, Maria, Riccio, Anna, Polimeno, Maria Neve, Monfregola, Luca, Barbieri, Antonio, Luciano, Antonio, Ciarmiello, Andrea, Arra, Claudio, Castello, Giuseppe, Amodeo, Pietro, Scala, Stefania
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772838/

id	pubmed-3772838
recordtype	oai_dc
spelling	pubmed-37728382013-09-20 Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases Portella, Luigi Vitale, Rosamaria De Luca, Stefania D’Alterio, Crescenzo Ieranò, Caterina Napolitano, Maria Riccio, Anna Polimeno, Maria Neve Monfregola, Luca Barbieri, Antonio Luciano, Antonio Ciarmiello, Andrea Arra, Claudio Castello, Giuseppe Amodeo, Pietro Scala, Stefania Research Article 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. Public Library of Science 2013-09-13 /pmc/articles/PMC3772838/ /pubmed/24058588 http://dx.doi.org/10.1371/journal.pone.0074548 Text en © 2013 Portella et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Portella, Luigi Vitale, Rosamaria De Luca, Stefania D’Alterio, Crescenzo Ieranò, Caterina Napolitano, Maria Riccio, Anna Polimeno, Maria Neve Monfregola, Luca Barbieri, Antonio Luciano, Antonio Ciarmiello, Andrea Arra, Claudio Castello, Giuseppe Amodeo, Pietro Scala, Stefania
spellingShingle	Portella, Luigi Vitale, Rosamaria De Luca, Stefania D’Alterio, Crescenzo Ieranò, Caterina Napolitano, Maria Riccio, Anna Polimeno, Maria Neve Monfregola, Luca Barbieri, Antonio Luciano, Antonio Ciarmiello, Andrea Arra, Claudio Castello, Giuseppe Amodeo, Pietro Scala, Stefania Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
author_facet	Portella, Luigi Vitale, Rosamaria De Luca, Stefania D’Alterio, Crescenzo Ieranò, Caterina Napolitano, Maria Riccio, Anna Polimeno, Maria Neve Monfregola, Luca Barbieri, Antonio Luciano, Antonio Ciarmiello, Andrea Arra, Claudio Castello, Giuseppe Amodeo, Pietro Scala, Stefania
author_sort	Portella, Luigi
title	Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
title_short	Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
title_full	Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
title_fullStr	Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
title_full_unstemmed	Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases
title_sort	preclinical development of a novel class of cxcr4 antagonist impairing solid tumors growth and metastases
description	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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772838/
_version_	1612011577867763712

Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases

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