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.

Abstract

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.

• Authors: Chinthalapally V Rao, Vernon E Steele, Malisetty V Swamy, Jagan M R Patlolla, Suresh Guruswamy, Levy Kopelovich
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 20 Pg. 8175-82 (Oct 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19826045 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carcinogens
• Cdkn1a protein, rat
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclooxygenase Inhibitors
• Membrane Proteins
• Pyrazoles
• Pyrimidines
• Sulfonamides
• Tumor Suppressor Protein p53
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, rat
• CP 31398
• Celecoxib
• Dinoprostone
• Azoxymethane

Topics

• Adenocarcinoma (chemically induced, metabolism, prevention & control)
• Animals
• Apoptosis (drug effects)
• Azoxymethane (toxicity)
• Blotting, Western
• Carcinogens (toxicity)
• Celecoxib
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (chemically induced, metabolism, prevention & control)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclooxygenase 1 (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (therapeutic use)
• Dinoprostone (metabolism)
• Drug Therapy, Combination
• Immunoenzyme Techniques
• In Situ Nick-End Labeling
• Male
• Maximum Tolerated Dose
• Membrane Proteins (metabolism)
• Pyrazoles (therapeutic use)
• Pyrimidines (therapeutic use)
• Rats
• Rats, Inbred F344
• Sulfonamides (therapeutic use)
• Tumor Suppressor Protein p53 (metabolism)