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.