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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | El-deiry, Wafik S. Kim, Seok-hyun Wang, Wenge |
| Spatial Coverage | United States |
| Description | Author Affiliation: Wang W ( Department 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 29 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antineoplastic Agents Therapeutic Use Colonic Neoplasms Drug Therapy Metabolism Signal Transduction Drug Effects Tumor Suppressor Protein P53 Deficiency Animals Chemistry Cell Cycle Cell Line, Tumor Genetics Pathology DNA DNA Damage Disease Models, Animal Drug Screening Assays, Antitumor Gene Expression Regulation, Neoplastic Genes, Reporter Luminescent Measurements Mice Mice, Inbred BALB C Mice, Nude Molecular Structure Mutation National Institutes Of Health (U.S.) Trans-Activators Classification Xenograft Model Antitumor Assays Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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