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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1312
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - May 2 2017

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Urokinase-Type Plasminogen Activator
Sarcoma
Cell Movement
Peptides
Biochemical Phenomena
Formyl Peptide Receptor
Physiological Phenomena
Neoplasm Metastasis
Circulating Neoplastic Cells
Molecular Dynamics Simulation
Microvessels
Nude Mice
Vascular Endothelial Growth Factor A
Blood Vessels
Neoplasms
Lung
Enzymes
Pharmaceutical Preparations
Therapeutics

Keywords

  • Journal Article

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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.

In: Scientific Reports, Vol. 7, No. 1, 02.05.2017, p. 1312.

Research output: Contribution to journalArticle

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. In: Scientific Reports. 2017 ; Vol. 7, No. 1. pp. 1312.
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