Abstract
Colorectal cancer is the fourth leading cause of cancer death worldwide, and it is important to establish effective methods for preventing colorectal cancer. One effective prevention strategy could be the use of antioxidants. However, the role of the direct antioxidative function of antioxidants against carcinogenesis has not been clarified. Thus, we aimed to determine whether the direct removal of reactive oxygen species by a hydroxyl radical scavenger, NZ-419, could inhibit colorectal carcinogenesis. NZ-419 is a creatinine metabolite that has been shown to be safe and to inhibit the progression of chronic kidney disease in rats, and it is now under clinical development. In the present study, we demonstrated that NZ-419 eliminated reactive oxygen species production in HCT116 cells after H2O2 stimulation and suppressed H2O2-induced Nrf2 promoter transcriptional activity. The administration of 500 ppm NZ-419 to Apc-mutant Min mice for 8 weeks resulted in a decrease in the number of polyps in the middle segment of the small intestine to 62.4% of the value in the untreated control (p < 0.05 vs. control group). As expected, NZ-419 treatment affected the levels of reactive carbonyl species, which are oxidative stress markers in the serum of Min mice. Suppression of the mRNA levels of the proliferation-associated factor c-Myc was observed in intestinal polyps of Min mice after NZ-419 treatment, with a weak suppression of epithelial cell proliferation assessed by proliferation cell nuclear antigen (PCNA) staining in the intestinal polyps. This study demonstrated that NZ-419 suppress the development of intestinal polyps in Min mice, suggesting the utility of radical scavenger/antioxidants as a cancer chemopreventive agent.
Highlights
Colorectal cancer (CRC) currently accounts for approximately 8% of all cancer deaths and is the fourth leading cause of cancer deaths worldwide [1]
We demonstrated that NZ-419 eliminated reactive oxygen species (ROS) production in HCT116 cells after H2O2 stimulation and suppressed H2O2-induced Nrf2 promoter transcriptional activity in an in vitro setting
We evaluated the levels of oxidative stress markers, reactive carbonyl species (RCs), in the serum of NZ-419-treated Min mice, and find that the number of RCs were reduced by NZ-419 administration, that indicated NZ-419 worked in the mice
Summary
Colorectal cancer (CRC) currently accounts for approximately 8% of all cancer deaths and is the fourth leading cause of cancer deaths worldwide [1]. One potentially effective prevention strategy could be the use of chemopreventive agents such as antioxidants. PUFAs are highly peroxidizable and may reduce reactive oxygen species (ROS) levels It inhibits cyclooxygenase (COX) activity and acts as a direct ligand for G protein-coupled receptors (GPCRs) [2,3]. As another example, lutein has been reported to have a superior antioxidant ability to scavenge free radicals compared with other carotenoids. There are more antioxidant phytochemicals that show both antioxidant function and cancer preventive function [7,8,9,10] From these reports, antioxidants have potential as cancer chemopreventive agents in the colorectum, but the proportional contribution of antioxidative function to carcinogenesis has not yet been clarified
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