Preclinical and clinical studies have established evidence that
cyclooxygenase-2 (COX-2) inhibitors and
statins [hydroxy-3-methylglutaryl
CoA reductase (HMGR) inhibitors] inhibit colon
carcinogenesis. Chronic use of high doses of
COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of
atorvastatin (
Lipitor) and
celecoxib individually or in combination in an animal model of
familial adenomatous polyposis. Six-week-old male C57BL/6J-APCmin/+ mice were either fed diets containing 0 or 100 ppm
atorvastatin or 300 ppm
celecoxib, or a combination of both for approximately 80 days. Mice were sacrificed, and their intestines were scored for
tumors. Normal-seeming mucosa and intestinal
tumors were harvested and assayed for apoptosis (
terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2
protein expression and activity. We observed that 100 ppm
atorvastatin significantly (P < 0.002) suppressed
intestinal polyp formation. As anticipated, 300 ppm
celecoxib decreased the rate of formation of
intestinal polyps by approximately 70% (P < 0.0001). Importantly, the combination of 100 ppm
atorvastatin and 300 ppm
celecoxib in the diet suppressed the colon
polyps completely and small
intestinal polyps by >86% (P < 0.0001) compared with the control group. The inhibition of
tumor formation by the
atorvastatin and
celecoxib combination was significant (P < 0.005) when compared with
tumor inhibition by
celecoxib alone. In addition, increased rates of apoptosis in intestinal
tumors (P < 0.01-0.0001) were observed in animals fed with
atorvastatin and
celecoxib and more so with the combinations.
Tumors of animals fed
atorvastatin showed a significant decrease in HMGR-R activity. Similarly,
tumors of mice exposed to
celecoxib showed significantly lower levels of COX-2 activity. These observations show that
atorvastatin inhibits intestinal
tumorigenesis and that, importantly, when given together with low doses of
celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice.