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 were 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 intraperitoneal administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate (NTA) 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 NTA significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells (RPMCs) to counteract asbestos-induced cytotoxicity than in RAW264.7. Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than RPMCs. 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 mesothelical carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.

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