Inhibition of Azoxymethane-Induced Colorectal Cancer by CP-31398, a TP53 Modulator, Alone or in Combination with Low Doses of Celecoxib in Male F344 Rats

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 20; pp. 8175 - 8182
• Main Authors: RAO, Chinthalapally V, STEELE, Vernon E, SWAMY, Malisetty V, PATLOLLA, Jagan M. R, GURUSWAMY, Suresh, KOPELOVICH, Levy
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2009
• Subjects: Adenocarcinoma - chemically induced; Adenocarcinoma - metabolism; Adenocarcinoma - prevention & control; Animals; Antineoplastic agents; Apoptosis - drug effects; Azoxymethane - toxicity; Biological and medical sciences; Blotting, Western; Carcinogens - toxicity; Celecoxib; Cell Proliferation - drug effects; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - prevention & control; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - therapeutic use; Dinoprostone - metabolism; Drug Therapy, Combination; Gastroenterology. Liver. Pancreas. Abdomen; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Maximum Tolerated Dose; Medical sciences; Membrane Proteins - metabolism; Pharmacology. Drug treatments; Pyrazoles - therapeutic use; Pyrimidines - therapeutic use; Rats; Rats, Inbred F344; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sulfonamides - therapeutic use; Tumor Suppressor Protein p53 - metabolism; Tumors; Prostaglandin-endoperoxide synthase; Rectal disease; Rat; Colorectal cancer; Male; Cyclooxygenase 2 inhibitor; TP53 Gene; Intestinal disease; Inhibition; Tumor suppressor gene; Drug combination; Modulator; Enzyme; Low dose; Rodentia; Enzyme inhibitor; Malignant tumor; Celecoxib; Colonic disease; Carcinogen; Vertebrata; Mammalia; Animal; Digestive diseases; Oxidoreductases; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1377

Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53-modulating agent CP-31398 alone and combined with celecoxib on azoxymethane-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3,000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on azoxymethane-treated 7-week-old rats (48 per group) fed the control AIN-76A diet. Two weeks after carcinogen treatment, rats were fed the diets containing 0, 150, or 300 ppm CP-31398, 300 ppm celecoxib, or 150 ppm CP-31398 plus 300 ppm celecoxib. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after azoxymethane treatment, respectively. Dietary CP-31398 was shown to suppress mean colonic total ACF by 43% and multicrypt ACF by 63%; dietary CP-31398 at 150 and 300 ppm suppressed adenocarcinoma incidence by 30.4% (P < 0.02) and 44% (P < 0.005), respectively, and adenocarcinoma multiplicity by 51% (P < 0.005) and 65% (P < 0.0001), respectively. Dietary celecoxib suppressed colon adenocarcinoma incidence (60%; P < 0.0003) and multiplicity (70%; P < 0.0001). Importantly, combination of low-dose CP-31398 and celecoxib suppressed colon adenocarcinoma incidence by 78% and multiplicity by 90%. Rats that were fed the high-dose CP-31398 or a combination of low-dose CP-31398 and celecoxib showed considerable enhancement of p53 and p21(WAF1/CIP) expression, apoptosis, and reduced tumor cell proliferation in colonic tumors. These observations show, for the first time, that CP-31398 possesses significant dose-dependent chemopreventive activity in a well-established colon cancer model and that a combination of low-dose CP-31398 and celecoxib significantly enhanced colon cancer chemopreventive efficacy.