title: Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma.
abstract: Pancreatic cancer is one of the intractable diseases and an effective therapeutic strategy is required to improve the prognosis. We examined possible antitumor effects of adenoviruses expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda-7) and a heat-shock protein 90 (Hsp90) inhibitor to human pancreatic carcinoma cells. Ad-mda-7 and an Hsp90 inhibitor, geldanamycin (GA), produced cytotoxic effects, and a combinatory use of Ad-mda-7 and GA further achieved synergistic effects. Administration of N-acetyl-L-cysteine, an inhibitor of reactive oxygen species, eliminated Ad-mda-7- and GA-mediated cytotoxicity. Ad-mda-7 augmented phosphorylated AKT levels but GA did not influence the phosphorylation. GA-treated cells showed cleavage of poly-(ADP-ribose) polymerase but not caspase-3, and upregulated Hsp70 and LC3A/B II levels, whereas Ad-mda-7-treated cells did not. GA treatments augmented ubiquitination and markedly increased melanoma differentiation-associated gene-7 (MDA-7) expression levels. These findings suggest that Ad-mda-7-mediated cytotoxicity is dependent on reactive oxygen species but independent of apoptosis or autophagy, and that GA-mediated cytotoxicity was linked with caspase-independent apoptosis and/or autophagy. A mechanism underlying the combinatory effects of Ad-mda-7 and GA remained complex and the synergism is attributable to multiple factors including increased MDA-7 protein stability by GA.
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan [2] Department of Gynecology and Obstetrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, 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, Chuo-ku, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Thoracic Diseases, Chiba Cancer Center, Chuo-ku, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, 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: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan [3] Department of Immunology, Basic Medical College, Hebei Medical University, Shijiazhuang, China [4] Cell Therapy Center, The First Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medical College, Hebei Medical University, Shijiazhuang, China.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Gynecology and Obstetrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.affiliation: Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: B
authors.initials: B
authors.lastname: Shan
authors.affiliation: Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: SVP Translational Medicine, Intrexon Corporation, Germantown, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chada
authors.affiliation: 1] Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan [2] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D016227:Benzoquinones / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000235:genetics*; D004357:Drug Synergism; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D000099180:Interleukin-24
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007378:Interleukins; D047029:Lactams, Macrocyclic; D000099180:Interleukin-24; C001277:geldanamycin