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
| Autor: | Jagan M.R. Patlolla, Chinthalapally V. Rao, Vernon E. Steele, Malisetty V. Swamy, Levy Kopelovich, Suresh Guruswamy |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male Cancer Research medicine.medical_specialty Maximum Tolerated Dose Colorectal cancer Blotting Western Azoxymethane Apoptosis Adenocarcinoma Gastroenterology Article Dinoprostone Immunoenzyme Techniques chemistry.chemical_compound Internal medicine In Situ Nick-End Labeling medicine Animals Cyclooxygenase Inhibitors Carcinogen Cell Proliferation Sulfonamides business.industry Membrane Proteins Cancer medicine.disease Rats Inbred F344 digestive system diseases Rats Pyrimidines Endocrinology Oncology chemistry Celecoxib Cyclooxygenase 2 Carcinogens Cyclooxygenase 1 Pyrazoles Drug Therapy Combination Tumor Suppressor Protein p53 Colorectal Neoplasms business Aberrant crypt foci medicine.drug |
| Zdroj: | Cancer Research. 69:8175-8182 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-1377 |
| Popis: | 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 p21WAF1/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. [Cancer Res 2009;69(20):8175–82] |
| Databáze: | OpenAIRE |
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