Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis

Our plain-English summary of Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis, by L. Jiang, S.H. Chew, K. Nakamura, et al (Cancer Science, 2016).

The study

• Authors: L. Jiang, S.H. Chew, K. Nakamura, Y. Ohara, S. Akatsuka, S. Toyokuni
• Journal: Cancer Science
• Published: 2016;107(7):908-15
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a short-term experiment in rats combined with laboratory cell studies, done at Nagoya University in Japan. Thirty-five male Wistar rats were split into seven groups of five. Six groups received two injections of chrysotile or crocidolite asbestos into the abdominal cavity (10 mg in total). For each asbestos type, one group then received five weekly injections of desferal (an iron-removing drug), one received five weekly injections of nitrilotriacetate (NTA, which promotes iron-driven chemical reactions), and one received asbestos only. One group received saline only. Rats given desferal after asbestos showed less scarring of the abdominal lining, less iron deposited there, lower blood ferritin, and less of a marker of oxidative DNA damage (8-OHdG) in mesothelial cells. NTA had the opposite effects. In cell cultures, desferal protected rat mesothelial cells, but not mouse macrophages, from asbestos damage. It also slowed the growth of two rat sarcomatoid mesothelioma cell lines but not of normal rat mesothelial cells. The experiment did not test whether the rats developed mesothelioma. The authors concluded that desferal has anticarcinogenic potential, and they called for further studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Short-term (subacute) animal experiment in rats, combined with cell culture experiments
• Who was studied: 35 six-week-old male Wistar rats, divided into seven groups of five, studied at Nagoya University, Japan. The cell experiments used rat peritoneal mesothelial cells, mouse macrophages (RAW264.7) and two asbestos-induced rat sarcomatoid mesothelioma cell lines (SM1 and SM2).
• Exposure: Chrysotile or crocidolite asbestos was injected into the peritoneal (abdominal) cavity, in two doses of 5 mg (10 mg total) during the first week. Some asbestos-treated groups then received weekly injections of nitrilotriacetate (80 mg/kg) or desferal (100 mg/kg) for 5 weeks, starting in the second week. The other asbestos-treated groups received asbestos only. A control group received saline.
• Main results:
  • Repeated NTA treatment after asbestos reduced the rats' body weight. Rats given desferal did not differ significantly in body weight from the saline control group.
  • In asbestos-injected rats, desferal markedly reduced fibrosis on the serosal surface of the spleen and liver, while NTA increased it. The authors reported that the fibrosis index confirmed these differences were statistically significant.
  • Desferal reduced stainable iron on the serosal surface of the liver and spleen, while NTA increased iron deposits.
  • Asbestos injection raised serum ferritin compared with saline controls. NTA raised it further, and desferal reduced it.
  • In mesothelial cells covering the spleen and liver, desferal decreased 8-OHdG staining (a marker of oxidative DNA damage) and NTA increased it. The authors reported that these differences were statistically significant.
  • In cell culture, desferal protected rat peritoneal mesothelial cells from asbestos-induced injury, but did not protect mouse macrophages.
  • Desferal inhibited the growth of the two rat sarcomatoid mesothelioma cell lines in a time- and dose-dependent manner. Similar results were seen after 48 hours of treatment with 15 to 30 micromolar desferal. No similar effect was seen in normal rat peritoneal mesothelial cells.
  • Adding iron in the form of holotransferrin partly reversed desferal's growth-slowing effect on the mesothelioma cell lines.
• The authors' conclusion: The authors concluded that desferal has anticarcinogenic potential against asbestos-induced carcinogenesis in two ways: by reducing inflammation and by reducing cell proliferation.
• Limitations the authors state:
  • Applying this technique to humans is limited because intrapleural administration is invasive.
  • Whether desferal actually prevents asbestos-induced mesothelial carcinogenesis in living animals remains to be determined by further studies.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Malignant Mesothelioma, Peritoneal Mesothelioma, Histology, Sarcomatoid, Epithelioid, Inflammation, Deposition.

Related studies

• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)
• Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis — S. Toyokuni (2014)
• The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy — S. Toyokuni (2016)
• Free radical activity of synthetic vitreous fibers: iron chelation inhibits hydroxyl radical generation by refractory ceramic fiber — D.M. Brown, C. Fisher, et al. (1998)
• Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model — D. Minami, N. Takigawa, et al. (2015)

Browse more research in Cancer Science, or return to medical research.