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

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.

rBMSC/Cav-1F92A Mediates Oxidative Stress in PAH Rat by Regulating SelW/14-3-3η and CA1/Kininogen Signal Transduction

“…The abnormal expression and activity of CA1, a zinc-containing metalloenzyme that belongs to the carbonic anhydrase family, result in excessive oxidative stress and disrupt redox homeostasis [22]. CA1 participates in ischemic-induced cardiac fibroblast development, hyperglycemia-induced endothelial cell death, cell proliferation, proinflammatory cytokine production, and vascular permeability alterations, which can be suppressed by a CA1 inhibitor [9, 26]. CA1 contributes to vascular injury by activating the plasma kallikrein system [11].…”

Vascular homeostasis at high‐altitude: role of genetic variants and transcription factors

“…Likewise, acetazolamide controls transcriptional activation of several TFs namely, AP-1, HIF, HSF, NF-κB, NRF2, p53, and STAT3. 120 Also, the corticosteroid action involves binding to several TFs including AP-1 or NF-κB as well recruitment of HDACs. 121…”

“…Likewise, acetazolamide controls transcriptional activation of several TFs namely, AP-1, HIF, Heat shock factor (HSF), Nuclear factor-kappa B (NF-κB), Nuclear factor erythroid 2-related factor 2 (NRF2), Tumor suppresor p53 (p53), and STAT3. 120 Also, the corticosteroid action involves binding to several TFs including AP-1 or NF-κB as well recruitment of HDACs. 121 Thus, recent advances surely encourage to envisage equally greater role for the various TFs in conjunction with the genetic variants in shaping a physiological path.…”

Evaluation of anti-cancer activity of Brinzolamide with special emphasis on blood cancer (Polycethemia Rubra Vera) in vivo

“…Rationale: Carbonic Anhydrase II is an important enzyme for the human body playing key role in regulation of apoptosis. [14] Literatures revels that Carbonic Anhydrase Inhibitors is induce the apoptosis of the cell and also reduce the cancer cell proliferation. [14] Apart from this, it is well reported that CA II level is raised in myeloid tissues and CA II inhibitors can play significant role in inhibition of progression of myeloid tissue.…”

“…[14] Literatures revels that Carbonic Anhydrase Inhibitors is induce the apoptosis of the cell and also reduce the cancer cell proliferation. [14] Apart from this, it is well reported that CA II level is raised in myeloid tissues and CA II inhibitors can play significant role in inhibition of progression of myeloid tissue. [16] Sulfonamide are having anti-cancer potential and can inhibit progression of Cancer.…”