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Cancer Biol Ther. 2002 Jan-Feb;1(1):47-55.

The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein.

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  • 1Howard Hughes Medical Institute, Departments of Medicine, Genetics, Pharmacology and Cancer Center, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB 437A, Philadelphia, Pennsylvania 19104, USA.

Abstract

CP-31398, a styrylquinazoline, emerged from a screen for therapeutic agents that restore a wild-type DNA-binding conformation of mutant p53 to suppress tumors in-vivo (Science 286, 2507, 1999). We investigated the growth inhibitory mechanism of CP-31398 using nine human cancer cell lines containing wild-type, mutant or no p53 expression. Six of nine cell lines underwent apoptosis after exposure to CP-31398, while two cell lines, DLD1 colon cancer and H460 lung cancer, underwent exclusively cell cycle arrest. Cell cycle arrest preceded the apoptosis in some cases. CP-31398 did not inhibit growth of the p53 non-expressing ovarian cancer cell line SKOV3. Interestingly, we found that wild-type p53 protein is stabilized upon CP-31398 exposure. p53 target genes such as p21WAF1/Cip1, and KILLER/DR5 were upregulated by CP-31398, but their expression did not correlate with arrest or apoptosis induction. Combination of CP-31398 and TRAIL or chemotherapeutic agents enhanced cancer cell killing effect possibly through upregulation of p53-regulated genes such as KILLER/DR5. Bax-/-, wild-type p53-expressing cells displayed reduced susceptibility to killing by CP-31398. An Affymetrix GeneChip Array screen revealed that CP-31398 alters expression of non-p53 target genes in addition to p53-responsive genes. Although our preliminary data suggest that CP-31398 does not alter wild-type p53:MDM2 interaction, further efforts are required to elucidate the mechanism of wild-type p53 stabilization by CP-31398. The results increase our understanding of CP-31398 action, and suggest strategies for improving its specificity, possibly through use of microarrays to screen related compounds with higher mutant p53-specificity.

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PMID:
12174820
[PubMed - indexed for MEDLINE]

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