Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.
Proc Natl Acad Sci U S A
; 103(6): 1888-93, 2006 Feb 07.
Article
in En
| MEDLINE
| ID: mdl-16443686
ABSTRACT
The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
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Signal Transduction
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2
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Imidazoles
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Neoplasms
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Antineoplastic Agents
Limits:
Animals
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Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2006
Document type:
Article
Affiliation country:
United States
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA