title: Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance.
abstract: The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer.
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Webb
authors.affiliation: b Department of Gynecology and Obstetrics ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Jori
authors.initials: J
authors.lastname: Carter
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: c Department of Medicine ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: c Department of Medicine ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: William P
authors.initials: WP
authors.lastname: McGuire
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: a Department of Biochemistry and Molecular Biology ; Virginia Commonwealth University ; Richmond , VA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D000077150:Oxaliplatin; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D000077150:Oxaliplatin; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; D000068677:Sildenafil Citrate; D000068579:Celecoxib; D002945:Cisplatin