title: Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib.
abstract: The proteasome inhibitor bortezomib (Velcade) is known to trigger endoplasmic reticulum (ER) stress via the accumulation of obsolete and damaged proteins. The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) causes ER stress through a different mechanism (i.e., by causing leakage of calcium from the ER into the cytosol). Each of these two mechanisms has been implicated in the anticancer effects of the respective drug. We therefore investigated whether the combination of these two drugs would lead to further increased ER stress and would enhance their antitumor efficacy. With the use of human glioblastoma cell lines, we show that this is indeed the case. When combined, bortezomib and celecoxib triggered elevated expression of the ER stress markers GRP78/BiP and CHOP/GADD153, caused activation of c-Jun NH(2)-terminal kinase and ER stress-associated caspase-4, and greatly increased apoptotic cell death. Small interfering RNA-mediated knockdown of the protective ER chaperone GRP78/BiP further sensitized the tumor cells to killing by the drug combination. The contribution of celecoxib was independent of the inhibition of COX-2 because a non-coxib analogue of this drug, 2,5-dimethyl-celecoxib (DMC), faithfully and more potently mimicked these combination effects in vitro and in vivo. Taken together, our results show that combining bortezomib with celecoxib or DMC very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity. We propose that this novel drug combination should receive further evaluation as a potentially effective anticancer therapy.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90089-9094, USA.
authors.forename: Adel
authors.initials: A
authors.lastname: Kardosh
authors.forename: Encouse B
authors.initials: EB
authors.lastname: Golden
authors.forename: Peter
authors.initials: P
authors.lastname: Pyrko
authors.forename: Jasim
authors.initials: J
authors.lastname: Uddin
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.forename: Stan G
authors.initials: SG
authors.lastname: Louie
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D000068579:Celecoxib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C506698:2,5-dimethylcelecoxib; D001897:Boronic Acids; D052246:Cyclooxygenase 2 Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D011719:Pyrazines; D011720:Pyrazoles; D013449:Sulfonamides; D000069286:Bortezomib; D000068579:Celecoxib