title: Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma.
abstract: We examined the combinatory antitumor effects of adenoviruses expressing human mda-7/IL-24 gene (Ad-mda-7) and chemotherapeutic agents on nine kinds of human esophageal carcinoma cells. All the carcinoma cells expressed the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) receptor complexes, IL-20R2 and either IL-20R1 or IL-22R1, and were susceptible to Ad-mda-7, whereas fibroblasts were positive only for IL-20R2 gene and resistant to Ad-mda-7-mediated cytotoxicity. Sensitivity of these esophageal carcinoma cells to Ad-mda-7 was however lower than that to Ad expressing the wild-type p53 gene. We thereby investigated a possible combination of Ad-mda-7 and anticancer agents and found that Ad-mda-7 with 5-fluorouracil (5-FU), cisplatin, mitomycin C or etoposide produced greater cytotoxic effects than those by Ad-mda-7 or the agent alone. Half-maximal inhibitory concentration values of the agents in respective cells were decreased by the combination with Ad-mda-7. Cell cycle analyses showed that Ad-mda-7 and 5-FU increased G2/M-phase and S-phase populations, respectively, and the combination augmented sub-G1 populations. Ad-mda-7-treated cells showed cleavages of caspase-8, -9 and -3 and poly (ADP-ribose) polymerase, but the cleavage levels were not different from those of the combination-treated cells. Ad-mda-7 treatments upregulated Akt phosphorylation but suppressed IκB-α levels, whereas 5-FU treatments induced phosphorylation of p53 and extracellular signal-regulated protein kinases 1 and 2. Molecular changes caused by the combination were similar to those by Ad-mda-7 treatments, but the Ad-mda-7-mediated upregulation of Akt phosphorylation decreased with the combination. These data collectively suggest that Ad-mda-7 induced apoptosis despite Akt activation and that the combinatory antitumor effects with 5-FU were produced partly by downregulating the Ad-mda-7-induced Akt activation.
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: G
authors.initials: G
authors.lastname: Ma
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shan
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: Niimi College, Niimi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Namba
authors.affiliation: Department of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: H
authors.identifier: 0000000219908217
authors.initials: H
authors.lastname: Shimada
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000276:immunology*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D000099180:Interleukin-24
chemical_list: D000970:Antineoplastic Agents; D007378:Interleukins; D018123:Receptors, Interleukin; D000099180:Interleukin-24