title: Brefeldin A induces apoptosis and cell cycle blockade in glioblastoma cell lines.
abstract: Brefeldin A (BFA), a fungal metabolite known to affect the structure and function of the Golgi apparatus, has recently been shown to induce apoptosis and cell growth inhibition in various human cell lines. Glioblastomas (GB) are cerebral tumors with poor prognosis, which display resistance to current therapies including radio- and chemotherapy. The objective of this study was to investigate BFA effects in three human GB cell lines (SA4, SA146 and U87MG cells). Compared with control cells, about 60% of cell growth inhibition was observed in BFA (100 ng/ml for 24 h)-exposed cells in the three cell lines. Furthermore, in SA4 and SA146 cells, BFA was able to induce a time- and dose-dependent apoptosis detected by DAPI staining, TUNEL assay and flow-cytometric analysis. Since p53 expression was not modified after BFA exposure, BFA-induced apoptosis may follow a p53-independent pathway, as already reported. In the same way, BFA did not alter Bcl-2, Bax and Mcl-1 expression. Cell cycle analysis revealed a cell cycle arrest in early G0/G1 phase with an increase in G0/G1 cell population (70% in control cells vs. 83% in exposed cells) associated with a decrease in the S cell population (14% in control cells vs. 5.5% in exposed cells). The Ki67 labeling index also confirmed the cell cycle blockade. Our results suggest that BFA may be a potent cell cycle modulator and inducer of apoptosis in GB cell lines, and therefore may become a promising candidate for the chemotherapeutic treatment of gliomas.
authors.affiliation: Department of Pathology, Limoges University Hospital, Faculty of Medicine, Limoges, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pommepuy
authors.forename: Faraj
authors.initials: F
authors.lastname: Terro
authors.forename: Barbara
authors.initials: B
authors.lastname: Petit
authors.forename: Frank
authors.initials: F
authors.lastname: Trimoreau
authors.forename: Virginie
authors.initials: V
authors.lastname: Bellet
authors.forename: Sandrine
authors.initials: S
authors.lastname: Robert
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
authors.forename: François
authors.initials: F
authors.lastname: Labrousse
authors.forename: Catherine
authors.initials: C
authors.lastname: Yardin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020126:Brefeldin A / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018942:Macrolides; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A