title: Primary ovarian cancer cells are sensitive to the proaptotic effects of proteasome inhibitors.
abstract: Resistance of tumors to cell death signals poses a complex clinical problem. In the present study, we have explored the capacity of proteasome inhibitors to induce cell death of ovarian cancer cells. We explored the sensitivity of primary ovarian cancer cells to a combination of bortezomib (also known as PS-341), a proteasome inhibitor and TRAIL, a death ligand, or mapatumumab or lexatumumab, TRAIL-R1 or TRAIL-R2 targeting agonist monoclonal antibodies, respectively. The results of our study showed that the large majority of primary ovarian cancers are clearly sensitive to the pro-apoptotic action of bortezomib, whose effects are potentiated by the concomitant addition of TRAIL or mapatumumab or lexatumumab. Interestingly, both cisplatin and paclitaxel-chemosensitive and chemoresistant ovarian tumors are equally sensitive to the cytotoxic effect of bortezomib. Bortezomib, combined with TRAIL or TRAIL-R1 or TRAIL-R2 agonist monoclonal antibodies may be a useful treatment for refractory ovarian cancer.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.forename: Alessia
authors.initials: A
authors.lastname: Petronelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Petrucci
authors.forename: Ernestina
authors.initials: E
authors.lastname: Saulle
authors.forename: Gualtiero
authors.initials: G
authors.lastname: Mariani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Benedetti-Panici
authors.forename: Stefano
authors.initials: S
authors.lastname: Greggi
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib