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Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.
Di Giorgio, Cristina; Bellini, Rachele; Lupia, Antonio; Massa, Carmen; Bordoni, Martina; Marchianò, Silvia; Rosselli, Rosalinda; Sepe, Valentina; Rapacciuolo, Pasquale; Moraca, Federica; Morretta, Elva; Ricci, Patrizia; Urbani, Ginevra; Monti, Maria Chiara; Biagioli, Michele; Distrutti, Eleonora; Catalanotti, Bruno; Zampella, Angela; Fiorucci, Stefano.
Afiliación
  • Di Giorgio C; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Bellini R; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Lupia A; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
  • Massa C; Net4Science srl, University "Magna Græcia", Catanzaro, Italy.
  • Bordoni M; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Marchianò S; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Rosselli R; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Sepe V; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
  • Rapacciuolo P; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
  • Moraca F; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
  • Morretta E; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
  • Ricci P; Net4Science srl, University "Magna Græcia", Catanzaro, Italy.
  • Urbani G; Department of Pharmacy, University of Salerno, Salerno, Italy.
  • Monti MC; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Biagioli M; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Distrutti E; Department of Pharmacy, University of Salerno, Salerno, Italy.
  • Catalanotti B; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Zampella A; Department of Gastroenterology, Azienda Ospedaliera di Perugia, Perugia, Italy.
  • Fiorucci S; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Front Oncol ; 13: 1140730, 2023.
Article en En | MEDLINE | ID: mdl-36998446
Introduction: The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1). Methods: Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. Results: The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM. Discussion: BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Oncol Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Oncol Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza