Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.

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.

• Authors: Christian Tovar, James Rosinski, Zoran Filipovic, Brian Higgins, Kenneth Kolinsky, Holly Hilton, Xiaolan Zhao, Binh T Vu, Weiguo Qing, Kathryn Packman, Ola Myklebost, David C Heimbrook, Lyubomir T Vassilev
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 6 Pg. 1888-93 (Feb 07 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16443686 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Piperazines
• Tumor Suppressor Protein p53
• nutlin 3
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects)
• Cell Line
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Imidazoles (pharmacology)
• Mice
• Mice, Nude
• Neoplasms (drug therapy, metabolism, pathology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays