title: Synergistic induction of apoptosis by mapatumumab and anthracyclines in human bladder cancer cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a variety of tumor cells by engaging the death receptors 4 (DR4) and 5 (DR5). We investigated the effect of chemotherapeutic drugs on DR4-mediated apoptosis in human bladder cancer cells, using a human monoclonal agonistic antibody specific for DR4, mapatumumab. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis. Treatment of human bladder cancer T24 cells with mapatumumab in combination with mitomycin C, vinblastine or gemcitabine did not overcome resistance to these agents. However, treatment with mapatumumab in combination with epirubicin (EPI) had a synergistic cytotoxic effect. Synergy was also obtained in KU7 and RT112 human bladder cancer cells. A synergistic effect was also observed with mapatumumab in combination with pirarubicin. The synergy obtained in cytotoxicity with mapatumumab and EPI was also achieved in apoptosis. EPI markedly increased DR4 expression in the bladder cancer cells at both the mRNA and protein levels. Furthermore, the combination-induced cytotoxicity was significantly suppressed by the DR4:Fc chimeric protein. The combination of EPI and mapatumumab significantly activated the caspase cascade, including caspase-8, -9 and -3, which are the downstream molecules of death receptors. These findings indicate that EPI sensitizes bladder cancer cells to DR4-mediated apoptosis through induction of DR4 and activation of caspases, suggesting that the combination therapy of EPI and mapatumumab may be effective for bladder cancer therapy.
authors.affiliation: Department of Urology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Syed Minhaj Uddin
authors.initials: SM
authors.lastname: Ahmed
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Xiuxian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Urology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Togo
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Yongnan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanematsu
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Nojima
authors.affiliation: Department of Urology, Hyogo Medical College, Nishinomiya City, Hyogo 663-8501, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Urology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Urology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kakehi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D015251:Epirubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D015251:Epirubicin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C507357:mapatumumab