Chemoprevention by Nimesulide, a Selective Cyclooxygenase‐2 Inhibitor, of 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP)‐induced Mammary Gland Carcinogenesis in Rats

Abstract

Breast cancer is common in women all over the world, and exploration of chemopreventive approaches to this cancer is very important. Nimesulide, a selective inhibitor of cyclooxygenase-2 (COX-2), is a good candidate as a chemopreventive agent with low toxicity. We examined its effects on mammary tumor development in female Sprague-Dawley rats induced with the environmental carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg/kg body weight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nimesulide) throughout the experiment. COX-2 protein was over-expressed in epithelial cancer cells and stromal cells of the PhIP-induced mammary carcinomas, but was weak or not apparent in normal mammary gland cells. The development of mammary carcinomas was clearly suppressed by administration of nimesulide. The carcinoma incidence was 51% as compared to 71% for the control diet group. The average multiplicity of carcinomas in the experimental diet group was 1.2 ± ± ± ±0.2 (P < < < <0.05), significantly smaller than the control diet group value (2.6 ± ± ± ±0.5). The size of carcinomas was also clearly decreased; 1.1 ± ± ± ±0.4 cm 3 /rat in experimental diet group (P < < < <0.05), 4.1 ± ± ± ±1.3 cm 3 /rat in the control diet group. The results therefore provide evidence that the selective COX-2 inhibitor, nimesulide, possesses chemopreventive activity against PhIPinduced mammary carcinogenesis in rats.Key words: Nimesulide -COX-2 inhibitor -Chemoprevention -Mammary gland cancer -PhIP Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to decrease prostanoid synthesis through inhibition of cyclooxygenase (COX) activity, 1) resulting in antiinflammatory effects. Two isoforms of cyclooxygenase-1 and -2 (COX-1 and COX-2) have been characterized in mammalian and avian species. COX-1 is constitutively expressed in most tissues to regulate prostaglandin (PG) production and maintain stable physiological conditions, including gastric cytoprotection and blood flow. In contrast, COX-2 is transiently induced by lipopolysaccharide, cytokines and growth factors, and has been indicated to produce large amount of prostanoids involved in inflammation and mitogenesis.2) COX-2 protein and mRNA are known to be expressed in not only inflammatory tissues, but also colorectal cancers in rats and humans.3, 4) Consistent with a causal role, regular use of aspirin has been shown to lower the risk of colon cancer in man. 5) Animal model studies have also demonstrated that NSAIDs, including aspirin and sulindac, can suppress colon carcinogenesis induced by azoxymethane (AOM) in rats.6, 7) In addition, NSAIDs have been shown to inhibit chemically induced mammary carcinogenesis in rats. 8, 9) Conventional NSAIDs such as aspirin, sulindac and indomethacin block both COX-1 and COX-2, resulting in unwanted side effects such as gastritis and gastric ulceration. However, selective CO...

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

“…Cell proliferation and migration were significantly reduced by EGCG at 100 μg/mL compared with the control (P<0.01). In PhIP-induced breast cancers, COX-2 and PGE 2 are closely related to estrogen biosynthesis through the aromatase gene (CYP), and these members may be involved in mammary gland carcinogenesis through the EP 1 receptor [26] . COX-2 acts as an oncogene under certain circumstances, leading to the production of PGE 2 which could then act in a paracrine or autocrine way to induce signaling via EP receptors, in particular the EP 1 receptor [27] .…”

COX inhibitors and breast cancer

“…Nimesulide reduced the size and numbers of carcinogen-induced tumours (Nakatsugi et al, 2000) and celecoxib inhibited the development of carcinogeninduced mammary tumours (Abou-Issa et al, 2001). Celecoxib has also been showed to significantly delay the onset of HER2/neuinduced tumours (Howe et al, 2002).…”

Prostanoid receptor EP1 expression in breast cancer

“…Nonsteroidal anti-inflammatory drugs (NSAIDs), which act through inhibition of cyclooxygenase enzyme (COX), are one such class of drugs that have been studied for their possible role in breast cancer prevention. Epidemiological studies investigating the relationship between NSAID use and breast cancer have reported conflicting results; some studies [3][4][5] show 30-40% reduction in breast cancer incidence with NSAID use, whereas others failed to confirm this relationship. 6,7 NSAIDs work by inhibiting both constitutive and inducible cyclooxygenase enzymes (COX-1 and COX-2, respectively), both of which have been postulated to play a role in carcinogenesis.…”