title: Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086.
abstract: WEB-2086 -- an antagonist of platelet-activating factor receptor (PAFR) with known anti-inflammatory, antiangiogenic and antileukaemic properties -- also proved to inhibit the proliferation in human solid tumour cell lines of different histology, and with much higher efficacy than in normal fibroblasts. A detailed analysis of WEB-2086 anticancer activity was then performed focusing on breast adenocarcinoma MCF-7 and MDA-MB-231 cells. WEB-2086-treated cells, either expressing (MCF-7) or unexpressing (MDA-MB-231) the oestrogen receptor (ER)alpha, underwent a dose-dependent growth arrest (IC(50)=0.65+/-0.09 and 0.41+/-0.07 mM, respectively) and accumulation in G(0)-G(1) phase. WEB-2086 also induced morphological and functional changes typical of mature mammary phenotype including (i) cell enlargement and massive neutral lipid deposition (best accomplished in MCF-7 cells); (ii) decrease in motility and active cathepsin D levels (mainly observed in highly invasive MDA-MB-231 cells). The expression of ERalpha was neither increased nor reactivated in treated MCF-7 or MDA-MB-231 cells, respectively. WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status. Overall, WEB-2086 can be proposed as an effective antiproliferative and differentiative agent with interesting translational opportunities to treat breast cancers in support to conventional chemotherapy.
authors.affiliation: Department of Experimental Pathology and Oncology, School of Medicine, University of Florence, Viale G. B. Morgagni 50, 50134 Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cellai
authors.forename: A
authors.initials: A
authors.lastname: Laurenzana
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: R
authors.initials: R
authors.lastname: Caporale
authors.forename: M
authors.initials: M
authors.lastname: Paglierani
authors.forename: S
authors.initials: S
authors.lastname: Di Lollo
authors.forename: A
authors.initials: A
authors.lastname: Pancrazzi
authors.forename: F
authors.initials: F
authors.lastname: Paoletti
mesh_terms: D001381:Azepines / Q000633:toxicity*; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D002402:Cathepsin D / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000633:toxicity*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D002402:Cathepsin D