title: Pharmacological inhibition of microsomal prostaglandin E synthase-1 suppresses epidermal growth factor receptor-mediated tumor growth and angiogenesis.
abstract: BACKGROUND
  Blockade of Prostaglandin (PG) E(2) production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE(2) promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway.
  
  
  RESULTS
  Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1β) increased mPGES-1 expression, PGE(2) production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE(2) production, both in quiescent and in cells stimulated by IL-1β. AF3485 abolished IL-1β-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice.
  
  
  CONCLUSIONS
  Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE(2) mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth.
authors: Department of Biotechnology, University of Siena, Via Aldo Moro, 2, Siena, and Istituto Toscano Tumori (ITT), Italy.
authors: Federica
authors: F
authors: Finetti
authors: Erika
authors: E
authors: Terzuoli
authors: Elena
authors: E
authors: Bocci
authors: Isabella
authors: I
authors: Coletta
authors: Lorenzo
authors: L
authors: Polenzani
authors: Giorgina
authors: G
authors: Mangano
authors: Maria Alessandra
authors: MA
authors: Alisi
authors: Nicola
authors: N
authors: Cazzolla
authors: Antonio
authors: A
authors: Giachetti
authors: Marina
authors: M
authors: Ziche
authors: Sandra
authors: S
authors: Donnini
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D000071876:Prostaglandin-E Synthases; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone