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.
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.
Rao
Chinthalapally V
CV
Department of Medicine, Hem-Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Steele
Vernon E
VE
Swamy
Malisetty V
MV
Patlolla
Jagan M R
JM
Guruswamy
Suresh
S
Kopelovich
Levy
L
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004359:Drug Therapy, Combination; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002273:Carcinogens; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C402665:CP 31398; D000068579:Celecoxib; D015232:Dinoprostone; D001397:Azoxymethane