title: Ibuprofen enhances TRAIL-induced apoptosis through DR5 upregulation.
abstract: Numerous human chemoprevention studies have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) possess chemopreventive effects against a variety of malignant tumors. However, there have been many clinical studies on aspirin, but not ibuprofen, even though ibuprofen is one of the most clinically and safely used NSAIDs showing potent anti-inflammatory effects. Moreover, we reported that many chemopreventive agents enhance the apoptosis-inducing effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is known to be crucial for cancer prevention. We, therefore, investigated whether ibuprofen enhances the cytocidal effect of TRAIL and found that ibuprofen markedly stimulated the apoptosis-inducing efficacy of TRAIL against human colon cancer HCT116 cells. As detected by western blot analysis and real-time RT-PCR, ibuprofen upregulated the expression of death receptor 5 (DR5), a TRAIL receptor. TRAIL-induced apoptosis enhanced by ibuprofen was effectively decreased by a caspase inhibitor and dominant-negative DR5. Noteworthy, co-treatment of ibuprofen with TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMCs). These results demonstrated that ibuprofen and TRAIL synergistically induced apoptosis in human colon cancer HCT116 cells but not in normal PBMCs, raising the possibility that ibuprofen may be promising as a safe chemopreventive agent against colon cancer.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Todo
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tomosugi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.forename: Haruna
authors.initials: H
authors.lastname: Ikawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D007052:Ibuprofen