title: Apoptotic effects of two COX-2 inhibitors on breast adenocarcinoma cells through COX-2 independent pathway.
abstract: Recently, much effort has been directed toward the search for compounds that influence apoptosis and to understand their mechanisms of action. Cyclooxygenase (COX)-2 inhibitors may induce apoptosis through the COX-2-independent mechanism via a mitochondrial pathway. In view of the reported antiproliferative activities of two COX-2 inhibitor derivatives (1, 2) in breast cancer cells (MCF-7), the present study was undertaken to evaluate the potential of these compounds to induce apoptosis and unravel the associated mechanisms. The apoptotic activities of the two compounds were assessed using flow cytometry, fluorescence microscope, and Western blot analysis. Compounds 1 and 2-treated MCF-7 cells revealed the apoptotic cell death, as confirmed by the changes in nuclear morphology and the increased annexin-V/PI staining. Elevation of Bax to Bcl-2 ratio and activation of caspase-3 were found to be associated with the initiation of apoptosis induced by compound 1. Further investigation showed that compounds 1 and 2 inhibited NF-κB, FHC, and ERK activation, while no dramatic change was revealed in c-Myc and EGR-1 levels. Our data suggest that induction of apoptosis by compounds 1 and 2 is not associated with COX-2 expression and occurs through the NF-κB pathway, which sequentially inhibits P-ERK and FHC expression.
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Science, Kharazmi University, Tehran, Iran.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Norouzi
authors.forename: Shaghayegh
authors.initials: S
authors.lastname: Norouzi
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
authors.forename: Amir
authors.initials: A
authors.lastname: Amanzadeh
authors.forename: Saeed
authors.initials: S
authors.lastname: Irian
authors.forename: Mona
authors.initials: M
authors.lastname: Salimi
mesh_terms: D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016328:NF-kappa B; D001052:Apoferritins
keywords: APOPTOSIS; CANCER; COX-2; MCF-7; NF-κB