Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

Abstract

Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction. Cancer Prev Res; 6(11); 1222-30. Ó2013 AACR.

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…Our results showed that although deferasirox treatment did not prevent MM development in the present experimental conditions, deferasirox significantly increased the fraction of rats with epithelioid subtype with favorable prognosis [149]. It is known that sarcomatoid MM is more aggressive and has a poorer prognosis compared to epithelioid subtype [32].…”

“…Thus, different sets of experiments are now in progress. Our results suggest that deferasirox may be potentially applied in the clinical prevention of MM development in individuals with known history of asbestos exposure [149]. In such a case, medical costs and side effects should also be considered.…”

“…Our results indicate that deferasirox administration extended the life span of rats with MM by modulating MM histopathological subtypes. Iron deposition was remarkably decreased in the deferasirox group [149], but the detailed mechanisms are yet to be determined. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 On the other hand, phlebotomy here did not show any difference from the untreated group, which might be attributed to technical difficulties in repeated phlebotomy in rodents.…”

Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis

“…This preclinical prevention study showed that lifetime deferasirox treatment after asbestos administration significantly increased the fraction of the epithelioid subtype of lower malignant potential. 58 Survival was marginally increased with deferasirox only in female rats. Repeated phlebotomy and its adjustment for the maximal effects are technically difficult in rats, and significant alteration was not observed with repeated phlebotomy for 1 year, which certainly requires further investigation.…”

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

“…Similarly, statins, which like some NSAIDS have been shown to reduce the chances of developing colorectal cancer, do not alter the incidence of MM in asbestos-exposed mice or humans [230]. Other experimental approaches involving iron reduction also showed limited efficacy in animal models [231]. So far, chemoprevention of MM has been as desirable as elusive.…”