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Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11003-8. Epub 2006 Jul 11.

Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts.

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  • 1Department of Medicine (Hematology/Oncology), Institute for Translational Medicine and Therapeutics, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Abstract

p53 deficiency is common in almost all human tumors and contributes to an aggressive chemo- or radiotherapy-resistant phenotype, therefore providing a target for drug development. Molecular targeting to restore wild-type p53 activity has been attempted in drug development and has led to the identification of CP-31398, PRIMA1, and the Nutlins. However, strategies targeting p53-activated transcriptional responses or p53 family member expression in p53-deficient tumors have yet to be explored. Here we demonstrate the use of noninvasive bioluminescence imaging in a high-throughput cell-based screen of small molecules that activate p53 responses and cell death in human tumor cells carrying a mutant p53. We isolated a number of small molecules that activate p53 reporter activity, increase expression of p53 target genes such as p21(WAF1) or death receptor 5 (KILLER/DR5) of TNF-related apoptosis-inducing ligand (TRAIL), and induce apoptosis in p53-deficient cells. Some of the compounds activate a p53 response by increasing p73 expression, and knockdown of transactivating isoforms of p73 by small interfering RNA reduces their induction of p53-responsive transcriptional activity. Some compounds do not induce significant p73 expression but induce a high p53-responsive transcriptional activity in the absence of p53. In vivo experiments demonstrate potent antitumor effects of selected compounds, using either HCT116/p53(-/-) or DLD1 human colon tumor xenografts. The results establish the feasibility of a cell-based drug screening strategy targeting the p53 transcription factor family of importance in human cancer and provide lead compounds for further development in cancer therapy.

PMID:
16835297
[PubMed - indexed for MEDLINE]
PMCID:
PMC1544164
Free PMC Article
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