Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APCmin/+ mice
Chinthalapally V Rao1, Malisetty V Swamy, Jagan M R Patlolla
1Department of Medicine, Hem-Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. cv-rao@ouhsc.edu
Abstract:
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.
Insights
The p53-modulating drug CP-31398 shows significant chemopreventive effects against intestinal adenomas in a mouse model. This compound suppressed tumor development and increased cell death, highlighting its potential for cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Chemoprevention
Background:
- p53 mutations are common in human cancers, impairing DNA repair, cell cycle control, and apoptosis.
- The styrylquinazoline CP-31398 can restore p53 function and promote wild-type p53 activity.
Purpose of the Study:
- To investigate the chemopreventive efficacy of CP-31398 against intestinal adenoma development.
- To evaluate CP-31398's effects at both early and late stages of adenoma formation in a familial adenomatous polyposis mouse model.
Main Methods:
- Mice (C57BL/6J-APC(min/+)) were fed diets containing 0, 100, or 200 ppm of CP-31398 starting at 7 weeks (early intervention) or 15 weeks (late intervention).
- Tumor development, apoptosis, proliferation, and expression of key proteins (p53, p21, cleaved caspase-3, cleaved PARP) were assessed.
Main Results:
- Early-stage intervention with CP-31398 suppressed intestinal tumors by 36% (low dose) and 75% (high dose).
- Late-stage intervention also reduced polyp formation, though to a lesser extent.
- Treated adenomas exhibited increased apoptosis, decreased proliferation, and elevated levels of p53, p21(WAF1/CIP), cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase.
Conclusions:
- CP-31398 demonstrates significant in vivo chemopreventive activity against intestinal neoplastic lesions in APC(min/+) mice.
- The drug's mechanism involves restoring p53 tumor suppressor function, leading to reduced proliferation and increased apoptosis.
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