Abstract
Metabolic syndrome (Mets), including diabetes and hypertension, increases the risk of colorectal cancer via the induction of chronic inflammation, acceleration of oxidative stress, and activation of the renin-angiotensin system. The present study examined the possible inhibitory effects of captopril, an angiotensin-converting enzyme (ACE) inhibitor and antihypertensive drug, on the development of azoxymethane (AOM)-induced colonic premalignant lesions, aberrant crypt foci (ACF), in SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic and hypertensive rats. Male 6-week-old SHRSP-ZF rats were administered two, weekly intraperitoneal injections of AOM (20 mg/kg body weight). Following the second injection, the rats received drinking water containing captopril (8 mg/kg/day) for two weeks. At sacrifice, captopril administration significantly lowered the blood pressure and reduced the total number and size of ACF compared with those observed in the untreated group. The serum levels of angiotensin-II and the expression levels of ACE and angiotensin-II type 1 receptor mRNA on the colonic mucosa decreased following captopril treatment. Captopril also reduced the urinary 8-hydroxy-2′-deoxyguanosine levels and the serum derivatives of reactive oxygen metabolites levels, both of which are oxidative stress markers, but increased the mRNA levels of catalase, an antioxidant enzyme, in the colonic epithelium. Moreover, the expression levels of tumor necrosis factor-α, interleukin-18, monocyte chemoattractant protein-1, inducible nitric oxide synthase, vascular endothelial growth factor and proliferating cell nuclear antigen mRNA in the colonic epithelium were decreased significantly following captopril administration. These observations suggested that captopril prevents the development of ACF by inhibiting renin-angiotensin system activation and attenuating inflammation and oxidative stress in SHRSP-ZF rats. Therefore, targeting Mets-related pathophysiological conditions, including renin-angiotensin system activation, may be an effective strategy to prevent colorectal carcinogenesis in patients with Mets, particularly those with hypertension.
Highlights
Colorectal cancer (CRC) is a serious health problem worldwide and recent evidence indicates that obesity and metabolic syndrome (Mets), both of which are global health problems, closely correlate with an increased risk of CRC development [1,2,3,4,5]
The colonic epithelial expression of proliferating cell nuclear antigen (PCNA) mRNA decreased significantly with captopril administration (Fig. 1C; P
Among pathophysiological disorders associated with Mets, in particular hypertension, activation of the renin‐angiotensin system is considered to be critical in the early events of colorectal carcinogenesis [10]
Summary
Colorectal cancer (CRC) is a serious health problem worldwide and recent evidence indicates that obesity and metabolic syndrome (Mets), both of which are global health problems, closely correlate with an increased risk of CRC development [1,2,3,4,5]. Several pathophysiological mechanisms, such as the emergence of insulin resistance, state of chronic inflammation and the induction of oxidative stress, may be involved in colorectal carcinogenesis in patients with Mets [3,4,5]. ACE inhibitors have been shown to exert beneficial effects on cardiovascular disease and reduce mortality as a result of hypertension [14,15]
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