title: Low concentrations of doxorubicin sensitizes human solid cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor (R) 2-mediated apoptosis by inducing TRAIL-R2 expression.
abstract: There is accumulating evidence suggesting that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor (R) 2 is a promising molecular target for cancer therapy. Therefore, we investigated the effect of chemotherapeutic agents on TRAIL-R2-mediated apoptosis and cytotoxicity in various human solid cancer cells. Treatment of the ACHN human renal cell carcinoma (RCC) cell line with agonistic TRAIL-R2 antibody (lexatumumab) in combination with 5-fluorouracil, vinblastine, paclitaxel, or docetaxel did not overcome resistance to these agents. However, treatment with lexatumumab in combination with doxorubicin had a synergistic cytotoxicity. Synergy was also achieved in two other human RCC cell lines, Caki-1 and Caki-2, and in eight primary RCC cell cultures. Sequential treatment with doxorubicin followed by lexatumumab induced significantly more cytotoxicity than reverse treatment or simultaneous treatment. Low concentrations of doxorubicin (0.1 and 1 microg/mL) significantly increased TRAIL-R2 expression at both the mRNA and protein levels. Furthermore, the combination of doxorubicin and lexatumumab significantly enhanced caspase 8 activity, Bid cleavage, Bcl-xL decrease, release of cytochrome c, and caspase 9 and caspase 3 activity, and induced synergistic apoptosis. The activation of caspases and apoptosis induced with lexatumumab and doxorubicin was blocked by the human recombinant DR5:Fc chimeric protein. In addition, synergistic cytotoxicity was also observed in human prostate, bladder, and lung cancer cells, but was inhibited by the DR5:Fc chimeric protein. These findings suggest that doxorubicin sensitizes solid cancer cells to TRAIL-R2-mediated apoptosis by inducing TRAIL-R2 expression, and that the combination treatment with lexatumumab and doxorubicin might be a promising targeted therapy for cancers, including RCC, prostate, bladder, and lung cancers.
authors.affiliation: Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan. wuxian@med.kagawa-u.ac.jp
authors.forename: Xiu-Xian
authors.initials: XX
authors.lastname: Wu
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Jin
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Ahmed Mamdouh Abd
authors.initials: AM
authors.lastname: El Hamed
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kakehi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D017931:DNA Primers; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D004317:Doxorubicin; C510234:lexatumumab; D020169:Caspases