The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
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DOI：
10.3390/jcm9010270
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Mutoh, Michihiro
中科院分区：
文献类型：
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作者：
Kurokawa, Yurie;Fujii, Gen;Mutoh, Michihiro
结直肠癌是全球第四大癌症死亡原因，建立有效的预防结直肠癌的方法非常重要。一种有效的预防策略是使用抗氧化剂。然而，抗氧化剂的直接抗氧化功能对抗癌的作用尚未明确。因此，我们的目的是确定通过羟自由基清除剂 NZ-419 直接去除活性氧是否可以抑制结直肠癌的发生。 NZ-419是一种肌酐代谢物，已被证明是安全的，并且可以抑制大鼠慢性肾病的进展，目前正处于临床开发阶段。在本研究中，我们证明NZ-419消除H2O2刺激后HCT116细胞中活性氧的产生，并抑制H2O2诱导的Nrf2启动子转录活性。对 Apc 突变 Min 小鼠施用 500 ppm NZ-419 8 周，小肠中段息肉数量减少至未治疗对照组的 62.4%（与对照组相比，p < 0.05）。正如预期的那样，NZ-419 治疗影响了活性羰基物质的水平，这些活性羰基物质是 Min 小鼠血清中的氧化应激标记物。 NZ-419治疗后，在Min小鼠的肠息肉中观察到增殖相关因子c-Myc mRNA水平受到抑制，通过肠息肉中的增殖细胞核抗原（PCNA）染色评估上皮细胞增殖受到微弱抑制。这项研究表明，NZ-419 可抑制 Min 小鼠肠息肉的发展，表明自由基清除剂/抗氧化剂可作为癌症化学预防剂。
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.