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.