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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

1
Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Division of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Sciences, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
3
Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
4
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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Abstract

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
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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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