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Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas

The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide...

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Autores principales: Carriero, Maria Vincenza, Bifulco, Katia, Ingangi, Vincenzo, Costantini, Susan, Botti, Giovanni, Ragone, Concetta, Minopoli, Michele, Motti, Maria Letizia, Rea, Domenica, Scognamiglio, Giosuè, Botti, Gerardo, Arra, Claudio, Ciliberto, Gennaro, Pessi, Antonello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430962/
https://www.ncbi.nlm.nih.gov/pubmed/28465589
http://dx.doi.org/10.1038/s41598-017-01425-9
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author Carriero, Maria Vincenza
Bifulco, Katia
Ingangi, Vincenzo
Costantini, Susan
Botti, Giovanni
Ragone, Concetta
Minopoli, Michele
Motti, Maria Letizia
Rea, Domenica
Scognamiglio, Giosuè
Botti, Gerardo
Arra, Claudio
Ciliberto, Gennaro
Pessi, Antonello
author_facet Carriero, Maria Vincenza
Bifulco, Katia
Ingangi, Vincenzo
Costantini, Susan
Botti, Giovanni
Ragone, Concetta
Minopoli, Michele
Motti, Maria Letizia
Rea, Domenica
Scognamiglio, Giosuè
Botti, Gerardo
Arra, Claudio
Ciliberto, Gennaro
Pessi, Antonello
author_sort Carriero, Maria Vincenza
collection PubMed
description The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target. We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis. To develop enzyme-resistant analogues, we applied here the Retro-Inverso (RI) approach, whereby the topology of the side chains is maintained by inverting the sequence of the peptide and the chirality of all residues. Molecular dynamics suggests that peptide RI-3 adopts the turn structure typical of uPAR-FPR1 antagonists. Accordingly, RI-3 is a nanomolar competitor of N-formyl-Met-Leu-Phe for binding to FPR1 and inhibits migration, invasion, trans-endothelial migration of sarcoma cells and VEGF-triggered endothelial tube formation. When sarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density, circulating tumor cells and pulmonary metastases were significantly reduced in animals treated daily with 6 mg/Kg RI-3 as compared to animals treated with vehicle only. Thus, RI-3 represents a promising lead for anti-metastatic drugs.
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spelling pubmed-54309622017-05-16 Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas Carriero, Maria Vincenza Bifulco, Katia Ingangi, Vincenzo Costantini, Susan Botti, Giovanni Ragone, Concetta Minopoli, Michele Motti, Maria Letizia Rea, Domenica Scognamiglio, Giosuè Botti, Gerardo Arra, Claudio Ciliberto, Gennaro Pessi, Antonello Sci Rep Article The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target. We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis. To develop enzyme-resistant analogues, we applied here the Retro-Inverso (RI) approach, whereby the topology of the side chains is maintained by inverting the sequence of the peptide and the chirality of all residues. Molecular dynamics suggests that peptide RI-3 adopts the turn structure typical of uPAR-FPR1 antagonists. Accordingly, RI-3 is a nanomolar competitor of N-formyl-Met-Leu-Phe for binding to FPR1 and inhibits migration, invasion, trans-endothelial migration of sarcoma cells and VEGF-triggered endothelial tube formation. When sarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density, circulating tumor cells and pulmonary metastases were significantly reduced in animals treated daily with 6 mg/Kg RI-3 as compared to animals treated with vehicle only. Thus, RI-3 represents a promising lead for anti-metastatic drugs. Nature Publishing Group UK 2017-05-02 /pmc/articles/PMC5430962/ /pubmed/28465589 http://dx.doi.org/10.1038/s41598-017-01425-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Carriero, Maria Vincenza
Bifulco, Katia
Ingangi, Vincenzo
Costantini, Susan
Botti, Giovanni
Ragone, Concetta
Minopoli, Michele
Motti, Maria Letizia
Rea, Domenica
Scognamiglio, Giosuè
Botti, Gerardo
Arra, Claudio
Ciliberto, Gennaro
Pessi, Antonello
Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title_full Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title_fullStr Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title_full_unstemmed Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title_short Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
title_sort retro-inverso urokinase receptor antagonists for the treatment of metastatic sarcomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430962/
https://www.ncbi.nlm.nih.gov/pubmed/28465589
http://dx.doi.org/10.1038/s41598-017-01425-9
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