cp-31398 and Ovarian-Neoplasms

The hen is an attractive animal model for in vivo testing of agents that thwart ovarian carcinogenesis because ovarian cancer in the domestic hen features clinical and molecular alterations that are similar to ovarian cancer in humans, including a high incidence of p53 mutations. The objective of the study was to test the potential ovarian cancer chemopreventive effect of the p53 stabilizing compound CP-31398 on hens that spontaneously present the ovarian cancer phenotype. Beginning at 79 wk of age, 576 egg-laying hens (Gallus domesticus) were randomized to diets containing different amounts of CP-31398 for 94 wk, 5 d, comprising a control group (C) (n = 144), which was fed a diet containing 0 ppm (mg/kg) of CP-31398; a low-dose treatment (LDT) group (n = 144), which was fed a diet containing 100 ppm of CP-31398; a moderate-dose treatment (MDT) group (n = 144) which was fed a diet containing 200 ppm of CP-31398; and a high-dose treatment (HDT) group (n = 144), which was fed a diet containing 300 ppm of CP-31398. Hens were killed at 174 wk of age to determine the incidence of ovarian and oviductal adenocarcinomas. Whereas the incidence of localized and metastatic ovarian cancers in the MDT and HDT groups was significantly lower (up to 77%) compared to levels in the C and LDT groups (P < 0.05), the incidence of oviductal cancer was unaffected by CP-31398. CP-31398 appears to be an effective tool for chemoprevention against ovarian malignancies, but does not appear to affect oviductal malignancies.

Topics: Adenocarcinoma; Animal Feed; Animals; Chemoprevention; Chickens; Diet; Female; Genes, p53; Genital Neoplasms, Female; Ovarian Neoplasms; Oviducts; Oviposition; Pyrimidines

CP-31398, a styrylquinazoline, emerged from a high throughput screen for therapeutic agents that restore a wild-type-associated epitope (monoclonal antibody 1620) on the DNA-binding domain of the p53 protein. We found that CP-31398 can not only restore p53 function in mutant p53-expressing cells but also significantly increase the protein level and promote the activity of wild-type p53 in multiple human cell lines, including ATM-null cells. Cells treated with CP-31398 undergo either cell cycle arrest or apoptosis. Further investigation showed that CP-31398 blocks the ubiquitination and degradation of p53 but not in human papillomavirus E6-expressing cells. Of note, CP-31398 does not block the physical association between p53 and MDM2 in vivo. Moreover, unlike the DNA-damaging agent adriamycin, which induces strong phosphorylation of p53 on serines 15 and 20, CP-31398 exposure leads to no measurable phosphorylation on these sites. We found that CP-31398 could also stabilize exogenous p53 in p53 mutant, wild-type, and p53-null human cells, even in MDM2-null p53(-/-) mouse embryonic fibroblasts. Our results suggest a model wherein CP-31398-mediated stabilization of p53 may result from reduced ubiquitination, leading to high levels of transcriptionally active p53. Further understanding of this mechanism may lead to novel strategies for p53 stabilization and tumor suppression in cancers, even those with absent ARF or high MDM2 expression.

Topics: Adenocarcinoma; Animals; Ataxia Telangiectasia Mutated Proteins; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA Damage; DNA-Binding Proteins; Doxorubicin; Female; Fibroblasts; Gene Expression Regulation; Genes, p53; Humans; Lung Neoplasms; Lymphocytes; Mice; Mice, Knockout; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Viral; Ovarian Neoplasms; Phosphorylation; Phosphoserine; Protein Binding; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Repressor Proteins; Transcription, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin