Candesartan Suppresses Intestinal Carcinogenesis Partly Through Inhibition of Plasminogen Activator Inhibitor1- Expression
*Michihiro Mutoh Department Of Oncology And Pathology, National Cancer Center Research Institute, Japan
*Corresponding Author: Michihiro Mutoh
Department Of Oncology And Pathology, National Cancer Center Research Institute, Japan Email:firstname.lastname@example.org
Published on: 2014-08-14
Obesity is a major cause of metabolic syndrome and is a convincing risk factor for colorectal cancer. The renin-angiotensin system (RAS) is activated in obese individuals and has been suggested to play important roles in development of hypertension and several cancers. To cast light on the significance of RAS for obesity-associated colorectal carcinogenesis, we examined the effects of an angiotensin II receptor blocker, candesartan, on colorectal carcinogenesis using obese KK-Ay mice and Apc-mutant Min mice. Six-week-old female KK-Ay mice were treated with 200 μg/mouse azoxymethane (AOM) once a week for 3 weeks and given 20 and 50 ppm candesartan in their drinking water, starting 2 days after the last AOM treatment. The numbers of colorectal aberrant crypt foci (ACF) and dysplastic ACF were decreased around 20% and 30%, respectively, in KK-Ay mice treated with 50 ppm candesartan compared with untreated mice. The dose of 50 ppm also reduced the number of PCNA-positive epithelial cells and the expression of c-myc in intestinal mucosa. Furthermore, mRNA expression of plasminogen activator inhibitor-1 (Pai-1) in visceral fat tissue was significantly decreased along with the reduction of visceral adipocyte size. In Min mice, formation of intestinal polyps was suppressed with a decrease of mRNA expression of Pai-1 in visceral fat tissue. These results indicated that candesartan could suppress obesity-associated colorectal carcinogenesis through improvement of Pai-1 expression.
Obesity is a major cause of metabolic syndrome, characterized by hyperglycemia, hyperinsulinemia, dyslipidemia and hypertension, and is a risk factor for cardiovascular disease, type 2 diabetes and colorectal cancer. However, the mechanisms responsible for these associations, especially with regard to colorectal cancer, have yet to be fully elucidated. Adipocytokines, which are hormones / cytokines produced in adipose tissue, such as angiotensinogen (AGT), interleukin- 6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α) and adiponectin are suggested to play important roles in these disorders. Moreover, dysregulation of adipocytokine production due to the hyperplastic change of adipocytes may enhance such disorders.