Chemoprevention of Carcinogenic Progression to Esophageal Adenocarcinoma by the Manganese Superoxide Dismutase Supplementation

Abstract

Purpose: Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation. Experimental Design: Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid^reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining. Results: Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP. Conclusion: MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.Esophageal adenocarcinoma (EAC) has received considerable attention because of the dramatically increased incidence in the past 2 decades and the poor prognoses with a 5-year survival rate of 10% to 20% (1 -5). Currently, it is widely accepted that a cause-effect relationship exists between gastroesophageal reflux disease and EAC. Oxidative stress has been proposed to be closely related to the carcinogenic progression of reflux esophagitis, Barrett's metaplasia, and EAC. It has been shown that reactive oxygen species increase with the grade of reflux esophagitis and are highest in Barrett's esophagus (BE) in clinical patients (6). Several studies have also shown that reactive oxygen species cause DNA injury, such as strand breakage, alterations in guanine and thymine bases, and DNA cross-linkage (7,8). Therefore, oxidative DNA damage may contribute to the accumulation of genetic damage, and the accumulation of genetic and epigenetic aberrations produces one or more clones with metaplastic and/or malignant potential (9).In our previous studies using an external esophageal perfusion rat model (10 -13), we have shown significant increased levels of lipid peroxidation and 8-hydr...

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…As expected, MnTBAP 3À lacks efficacy in the O 2 ·À -specific model of aerobic growth of SOD-deficient E. coli (31,262). MnTBAP 3À (most likely in some impure form) has been used in numerous studies (73,76,194,206,229,251). Most of the reports assigned the effects observed in vivo to MnTBAP 3À SOD-like activity.…”

“…Although the effects observed may be real, mechanistic explanations attributing them to an SOD-like activity of MnTBAP 3À are likely not real (73,76,194,206,229,251). As already mentioned, either the effects are due to the SOD-like impurities or the MnTBAP 3À acts through ONOO À -mediated pathways.…”

Manganese Superoxide Dismutase in Cancer Prevention

“…In human esophageal cancers, studies have shown that decreased MnSOD levels are associated with increased incidences of esophageal adenocarcinoma (EAC) (82).…”

“…It has been demonstrated that metalloporphyrins with higher SOD activity have higher CAT activity suggesting the utility of SOD mimetics in ROS-mediated in vitro and in vivo models of disease (104). In an EAC rat model, the SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) decreased the incidence of EAC, which is correlated with a 25% increase in SOD enzymatic activities, suggesting MnTBAP may be able to serve as a chemopreventive agent for EAC (82). Another SOD mimetic (MnTE-2-PyP 5 + ) has been tested in the chemically-induced skin carcinogenesis mouse model (158).…”

The role of Hsp90 in PC-12 cell survival.

“…The metalloporphyrin manganese superoxide dismutase (MnSOD) mimetic, MnTBAP, is such an alternative antioxidant [174], that induces cancer cell death by increasing H 2 0 2 [173], yet inhibits cardiotoxicity induced by the anthraquinone derivative chemotherapeutic, Doxorubicin [175], and acute liver failure [176]. In addition, the antioxidant properties of MnTBAP may be chemopreventive against esophageal adenocarcinoma [177]. Alternatively, the recent development of the Hsp90-hinding non-quinone analog of GA, analog 5 of macbecin, may provide cancer therapies that are less toxic to normal cells [178].…”