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Pharmacological inhibition of PDGF-C/neuropilin-1 interaction: A novel strategy to reduce melanoma metastatic potential.
Ceci, Claudia; Ruffini, Federica; Falconi, Mattia; Atzori, Maria Grazia; Falzon, Andrea; Lozzi, Flavia; Iacovelli, Federico; D'Atri, Stefania; Graziani, Grazia; Lacal, Pedro Miguel.
Afiliação
  • Ceci C; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Ruffini F; Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy.
  • Falconi M; Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • Atzori MG; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Falzon A; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Lozzi F; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Iacovelli F; Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • D'Atri S; Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy.
  • Graziani G; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Lacal PM; Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy. Electronic address: p.lacal@idi.it.
Biomed Pharmacother ; 176: 116766, 2024 07.
Article em En | MEDLINE | ID: mdl-38788599
ABSTRACT
Activation of neuropilin-1 (NRP-1) by platelet derived growth factor (PDGF)-C sustains melanoma invasiveness. Therefore, in the search of novel agents capable of reducing melanoma spreading, PDGF-C/NRP-1 interaction was investigated as a potential druggable target. Since the PDGF-C region involved in NRP-1 binding is not yet known, based on the sequence and structural homology between PDGF-C and vascular endothelial growth factor-A (VEGF-A), we hypothesized that the NRP-1 b1 domain region involved in the interaction with VEGF-A might also be required for PDGF-C binding. Hence, this region was selected from the protein crystal structure and used as target in the molecular docking procedure. In the following virtual screening, compounds from a DrugBank database were used as query ligands to identify agents potentially capable of disrupting NRP-1/PDGF-C interaction. Among the top 45 candidates with the highest affinity, five drugs were selected based on the safety profile, lack of hormonal effects, and current availability in the market the antipsychotic pimozide, antidiabetic gliclazide, antiallergic cromolyn sodium, anticancer tyrosine kinase inhibitor entrectinib, and antihistamine azelastine. Analysis of drug influence on PDGF-C in vitro binding to NRP-1 and PDGF-C induced migration of human melanoma cells expressing NRP-1, indicated gliclazide and entrectinib as the most specific agents that were active at clinically achievable and non-toxic concentrations. Both drugs also reverted PDGF-C ability to stimulate extracellular matrix invasion by melanoma cells resistant to BRAF inhibitors. The inhibitory effect on tumor cell motility involved a decrease of p130Cas phosphorylation, a signal transduction pathway activated by PDGF-C-mediated stimulation of NRP-1.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator de Crescimento Derivado de Plaquetas / Linfocinas / Neuropilina-1 / Simulação de Acoplamento Molecular / Melanoma Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator de Crescimento Derivado de Plaquetas / Linfocinas / Neuropilina-1 / Simulação de Acoplamento Molecular / Melanoma Idioma: En Ano de publicação: 2024 Tipo de documento: Article