nutlin-1 and Neoplasms

P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53. One of the explanations to this is that p53 is suppressed by overexpression of p53-specific E3-ubiquitin ligases: Mdm2, MdmX, Pirh2 and Cop1. Pharmacological inhibition of protein-protein interactions between p53 and these negative regulators is a promising therapeutic approach to treat cancers retaining wild type p53. To date, a series of chemical inhibitors of p53 interactions with Mdm2 and MdmX E3-ubiquitin ligases have been discovered and characterized. Several of them are in the early stages of clinical trials. Despite this fact, their clinical efficacy may be hampered by a number of reasons, including tumor-specific expression of multiple isoforms of the target E3-ligases, which become inert to treatment with small molecules. This and other biochemical mechanisms of possible resistance of tumor cells with wild type p53 to small molecules against its negative regulators will be discussed in this review.

Topics: Antineoplastic Agents; Cell Cycle Proteins; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Neoplasms; Nuclear Proteins; Piperazines; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

p53 mutation occurs in over half of all human tumors. Among the remaining tumors, although they may process a wild-type p53, the pathways of p53-induced cell-cycle arrest and apoptosis are deficient. Therefore, p53 serves as a unique molecular target for cancer therapy. This review focuses on the current progress regarding restoration of p53 function in human tumors for molecularly targeted therapy.. Targeting p53 for cancer therapy has been intensively pursued. CP-31398 was the first small molecule identified with the ability to restore the wild-type conformation to mutant p53. Subsequently, PRIMA-1 and ellipticine were found to be able to induce mutant p53-dependent cell death. Nutlin was developed to rescue wild-type p53 from degradation mediated by MDM2. More recently, p53 family members can be activated and therefore serve as substitutes of p53 in tumor cells and induce cell death.. Loss of p53 function is a characteristic of almost all human tumors. Recent advances demonstrate that reconstitution of p53 function is possible and practical as a promising antitumor strategy.

Topics: Antineoplastic Agents; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Ellipticines; Genes, p53; Humans; Imidazoles; Models, Biological; Mutation; Neoplasms; Piperazines; Pyrimidines; Tumor Suppressor Protein p53

Topics: Animals; Antineoplastic Agents; Apoptosis; Drug Design; Gene Expression; Gene Expression Regulation; Humans; Imidazoles; Neoplasms; Piperazines; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Carrier Proteins; Humans; Imidazoles; Models, Molecular; Neoplasms; Piperazines; Protein Binding; Tumor Suppressor Protein p53

p53 regulates a key pathway which protects normal tissues from tumor development that may result from diverse forms of stress. In the absence of stress, growth suppressive and proapoptotic activity of p53 is inhibited by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 antagonists could activate p53 and may offer a novel therapeutic approach to cancer. Recently, we identified the first potent and selective low molecular weight inhibitors of MDM2-p53 binding, the Nutlins. These molecules activate the p53 pathway and suppress tumor growth in vitro and in vivo. They represent valuable new tools for studying the p53 pathway and its defects in cancer. Nutlins induce p53-dependent apoptosis in human cancer cells but appear cytostatic to proliferating normal cells. Their potent activity against osteosarcoma xenografts suggests that MDM2 antagonists may have clinical utility in the treatment of tumors with wild-type p53.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Division; Cell Line, Tumor; Cell Survival; Culture Media; Dose-Response Relationship, Drug; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitory Concentration 50; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Nuclear Proteins; Osteosarcoma; Piperazines; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53