title: Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis.
abstract: Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations are similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used i.p. administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition, and nuclear 8-hydroxy-2'-deoxyguanosine levels in mesothelial cells, whereas nitrilotriacetate significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells to counteract asbestos-induced cytotoxicity than in murine macrophages (RAW264.7). Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than rat peritoneal mesothelial cells. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelial carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shan-Hwu
authors.initials: SH
authors.lastname: Chew
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Ohara
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinya
authors.identifier: http://orcid.org/0000-0002-5757-1109
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D001835:Body Weight; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D000090463:Iron Deficiencies; D008264:Macrophages / Q000187:drug effects; D008297:Male; D018301:Neoplasms, Mesothelial / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007502:Iron Chelating Agents; D001194:Asbestos; D000080242:8-Hydroxy-2'-Deoxyguanosine; D007501:Iron; D003849:Deoxyguanosine; D003676:Deferoxamine
keywords: Asbestos; chelator; desferal; iron; mesothelioma