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

Abstract 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...

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Autores principales:	Maria Vincenza Carriero, Katia Bifulco, Vincenzo Ingangi, Susan Costantini, Giovanni Botti, Concetta Ragone, Michele Minopoli, Maria Letizia Motti, Domenica Rea, Giosuè Scognamiglio, Gerardo Botti, Claudio Arra, Gennaro Ciliberto, Antonello Pessi
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e00079ff18874aaea55c11698d809490
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spelling	oai:doaj.org-article:e00079ff18874aaea55c11698d8094902021-12-02T11:40:59ZRetro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas10.1038/s41598-017-01425-92045-2322https://doaj.org/article/e00079ff18874aaea55c11698d8094902017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01425-9https://doaj.org/toc/2045-2322Abstract 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.Maria Vincenza CarrieroKatia BifulcoVincenzo IngangiSusan CostantiniGiovanni BottiConcetta RagoneMichele MinopoliMaria Letizia MottiDomenica ReaGiosuè ScognamiglioGerardo BottiClaudio ArraGennaro CilibertoAntonello PessiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Vincenza Carriero Katia Bifulco Vincenzo Ingangi Susan Costantini Giovanni Botti Concetta Ragone Michele Minopoli Maria Letizia Motti Domenica Rea Giosuè Scognamiglio Gerardo Botti Claudio Arra Gennaro Ciliberto Antonello Pessi Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas
description	Abstract 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.
format	article
author	Maria Vincenza Carriero Katia Bifulco Vincenzo Ingangi Susan Costantini Giovanni Botti Concetta Ragone Michele Minopoli Maria Letizia Motti Domenica Rea Giosuè Scognamiglio Gerardo Botti Claudio Arra Gennaro Ciliberto Antonello Pessi
author_facet	Maria Vincenza Carriero Katia Bifulco Vincenzo Ingangi Susan Costantini Giovanni Botti Concetta Ragone Michele Minopoli Maria Letizia Motti Domenica Rea Giosuè Scognamiglio Gerardo Botti Claudio Arra Gennaro Ciliberto Antonello Pessi
author_sort	Maria Vincenza Carriero
title	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_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_sort	retro-inverso urokinase receptor antagonists for the treatment of metastatic sarcomas
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e00079ff18874aaea55c11698d809490
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Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas

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