Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APCmin/+ mice

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 18; pp. 7670 - 7675
• Main Authors: Rao, Chinthalapally V, Swamy, Malisetty V, Patlolla, Jagan M R, Kopelovich, Levy
• Format: Journal Article
• Language: English
• Published: United States 15-09-2008
• Subjects: Adenomatous Polyposis Coli - drug therapy; Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - metabolism; Adenomatous Polyposis Coli - pathology; Animals; Apoptosis - drug effects; Caspase 3 - metabolism; Cell Growth Processes - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Dose-Response Relationship, Drug; Female; Genes, APC; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - genetics; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Mice; Mice, Inbred C57BL; Poly(ADP-ribose) Polymerases - metabolism; Pyrimidines - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-1610

p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APC(min) (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP-31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21(WAF1/CIP), cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APC(min/+) mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation.