title: Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.
abstract: Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.
authors.affiliation: Laboratoire de Biologie Cellulaire, Laboratoire Santé, Travail, Environnement EA 3672, Université Victor Segalen, 146 rue Léo Saignat, 33 076 Bordeaux, France. stephane.pedeboscq@chu-bordeaux.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pédeboscq
authors.forename: Béatrice
authors.initials: B
authors.lastname: L'Azou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Passagne
authors.forename: Francesca
authors.initials: F
authors.lastname: De Giorgi
authors.forename: François
authors.initials: F
authors.lastname: Ichas
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pometan
authors.forename: Jean
authors.initials: J
authors.lastname: Cambar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005434:Flow Cytometry; D000077156:Gefitinib; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D051379:Mice; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D000077204:Temozolomide; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; D005904:Glial Fibrillary Acidic Protein; D007202:Indicators and Reagents; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011799:Quinazolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000069286:Bortezomib; D003606:Dacarbazine; D016190:Carboplatin; D066246:ErbB Receptors; C022616:thiazolyl blue; D000077156:Gefitinib; D002330:Carmustine; D000077204:Temozolomide