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The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice

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 aga...

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Autores principales: Kurokawa, Yurie, Fujii, Gen, Tomono, Susumu, Miyamoto, Shingo, Hamoya, Takahiro, Takahashi, Maiko, Narita, Takumi, Komiya, Masami, Kobayashi, Masaki, Higami, Yoshikazu, Mutoh, Michihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019572/
https://www.ncbi.nlm.nih.gov/pubmed/31963747
http://dx.doi.org/10.3390/jcm9010270
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author Kurokawa, Yurie
Fujii, Gen
Tomono, Susumu
Miyamoto, Shingo
Hamoya, Takahiro
Takahashi, Maiko
Narita, Takumi
Komiya, Masami
Kobayashi, Masaki
Higami, Yoshikazu
Mutoh, Michihiro
author_facet Kurokawa, Yurie
Fujii, Gen
Tomono, Susumu
Miyamoto, Shingo
Hamoya, Takahiro
Takahashi, Maiko
Narita, Takumi
Komiya, Masami
Kobayashi, Masaki
Higami, Yoshikazu
Mutoh, Michihiro
author_sort Kurokawa, Yurie
collection PubMed
description 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 H(2)O(2) stimulation and suppressed H(2)O(2)-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.
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spelling pubmed-70195722020-03-09 The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice Kurokawa, Yurie Fujii, Gen Tomono, Susumu Miyamoto, Shingo Hamoya, Takahiro Takahashi, Maiko Narita, Takumi Komiya, Masami Kobayashi, Masaki Higami, Yoshikazu Mutoh, Michihiro J Clin Med Article 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 H(2)O(2) stimulation and suppressed H(2)O(2)-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. MDPI 2020-01-18 /pmc/articles/PMC7019572/ /pubmed/31963747 http://dx.doi.org/10.3390/jcm9010270 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kurokawa, Yurie
Fujii, Gen
Tomono, Susumu
Miyamoto, Shingo
Hamoya, Takahiro
Takahashi, Maiko
Narita, Takumi
Komiya, Masami
Kobayashi, Masaki
Higami, Yoshikazu
Mutoh, Michihiro
The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title_full The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title_fullStr The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title_full_unstemmed The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title_short The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
title_sort radical scavenger nz-419 suppresses intestinal polyp development in apc-mutant mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019572/
https://www.ncbi.nlm.nih.gov/pubmed/31963747
http://dx.doi.org/10.3390/jcm9010270
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