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Int. J. Mol. Sci. 2017, 18(4), 851; doi:10.3390/ijms18040851

Impact of Acetazolamide, a Carbonic Anhydrase Inhibitor, on the Development of Intestinal Polyps in Min Mice

Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Division of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Sciences, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Author to whom correspondence should be addressed.
Academic Editors: Takuji Tanaka and Masahito Shimizu
Received: 10 March 2017 / Revised: 7 April 2017 / Accepted: 12 April 2017 / Published: 17 April 2017
(This article belongs to the Special Issue Inflammation and Cancer)
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Colorectal cancer is a common cancer worldwide. Carbonic anhydrase (CA) catalyzes the reversible conversion of carbon dioxide to bicarbonate ion and a proton, and its inhibitor is reported to reduce cancer cell proliferation and induce apoptosis. Therefore, we asked whether acetazolamide, a CA inhibitor, could inhibit intestinal carcinogenesis. Five-week-old male Apc-mutant mice, Min mice, were fed a AIN-76A diet containing 200 or 400 ppm acetazolamide. As a result, acetazolamide treatment reduced the total number of intestinal polyps by up to 50% compared to the control group. In addition, the acetazolamide-treated group had low cell proliferation and a high apoptosis ratio in the intestinal polyp epithelial cells. Moreover, the mRNA expression level of proinflammatory cytokines, such as IL-6, involved in the cell proliferation was decreased in the polyp part of the acetazolamide-treated group. Next, we examined the effects of acetazolamide on the activation of several transcriptional factors (AP-1, HIF, HSF, NF-κB, NRF2, p53, and STAT3) using a reporter gene assay in human colon cancer cells, Caco-2 cells. Among the examined transcriptional factors, NRF2 transcriptional activation was strongly induced. NRF2-targeting genes, γGCS, GPx1, HO-1, and NQO-1, were also elevated in the intestinal polyps of acetazolamide-treated Min mice. Our results suggested that CA is involved in intestinal carcinogenesis. Acetazolamide could inhibit polyp formation through suppressing local/general cytokine levels, i.e., IL-6, via NRF2 activation. View Full-Text
Keywords: carbonic anhydrase; acetazolamide; NRF2; IL-6; colorectal cancer chemoprevention carbonic anhydrase; acetazolamide; NRF2; IL-6; colorectal cancer chemoprevention

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Noma, N.; Fujii, G.; Miyamoto, S.; Komiya, M.; Nakanishi, R.; Shimura, M.; Tanuma, S.-I.; Mutoh, M. Impact of Acetazolamide, a Carbonic Anhydrase Inhibitor, on the Development of Intestinal Polyps in Min Mice. Int. J. Mol. Sci. 2017, 18, 851.

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