cp-31398 and 2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one

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

p53 is a molecule which is activated upon a DNA stress, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading protection of cells by inducing target genes. The molecules activated by p53 induce apoptosis, cell cycle arrest, and DNA repair to conserve genome. In order to kill cancer cells, many strategies targeting p53 have been reported. Preclinical studies have demonstrated that overexpression of wt-p53 by adenovirus vector is capable of inducing apoptosis in cancers. Furthermore, restoration of mt-p53 into wild type by compound has been under development. In this review, clinical application of molecular targeting therapy for p53 is discussed.

Topics: Apoptosis; Aza Compounds; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Fas Ligand Protein; Gene Targeting; Genes, p53; Genetic Therapy; Humans; Membrane Glycoproteins; Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Tumor Suppressor Protein p53

Around half of all human tumours carry mutant p53. This allows escape from p53-induced cell cycle arrest and apoptosis. Many tumours express mutant p53 proteins at elevated levels. Restoration of wild-type p53 function should trigger massive apoptosis in tumour cells and thus eradicate tumours. Various types of small molecules have been identified that can restore native conformation and wild-type function to mutant p53. Such molecules may serve as leads for the development of novel efficient anticancer drugs.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Ellipticines; Gene Expression Regulation, Neoplastic; Genes, p53; Genetic Therapy; Humans; Mercaptoethylamines; Molecular Chaperones; Mutation; Neoplasms; Pyrimidines

Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest.

Topics: Animals; Antineoplastic Agents; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Pyrimidines; Tumor Suppressor Protein p53

The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.

Topics: Alkylation; Amifostine; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Evaluation, Preclinical; Ellipticines; Heterocyclic Compounds, 4 or More Rings; Humans; Kinetics; Ligands; Mercaptoethylamines; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Mutation; Oxepins; Protein Binding; Pyrimidines; Quinuclidines; Tumor Suppressor Protein p53

Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Transformation, Neoplastic; Chemoprevention; Cyclin-Dependent Kinase Inhibitor p21; Female; Lung Neoplasms; Mice; Mice, Inbred A; Nicotiana; Nitrosamines; Pyrimidines; Random Allocation; Tumor Suppressor Protein p53

Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.

Topics: Adolescent; Adult; Aza Compounds; Biomarkers, Tumor; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Ductal, Breast; Cells, Cultured; Epithelial Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Germ-Line Mutation; Haploinsufficiency; Humans; Li-Fraumeni Syndrome; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stromal Cells; Tumor Suppressor Protein p53

p53 is a major target for tumor therapy. Attempts have been made to restore or enhance p53 activity in tumor cells, including overexpression of exogenous p53 and small molecules that can rescue mutant p53. Notably, p53 peptides corresponding to the p53 carboxyl terminus can trigger a p53 response in both wild-type or mutant p53-containing cells. The recent protein transduction domain (PTD)-mediated cell entry might solve the obstacle of efficient delivery of peptides or large molecular biological cargos into cells. PTD-mediated transfer through the cell membrane occurs through a kind of endocytosis, macropinocytosis. Destabilization of macropinocytosomes by the influenza virus hemagglutinin protein (HA2) helps the escape of the PTD-cargo from macropinocytosomes and therefore significantly enhances the functional impact of transduced cargo.

Topics: Antineoplastic Agents; Aza Compounds; Binding Sites; Biological Transport; Bridged Bicyclo Compounds, Heterocyclic; Drug Carriers; Gene Products, tat; Genetic Therapy; Hemagglutinins, Viral; Humans; Hydrogen-Ion Concentration; Intracellular Membranes; Models, Biological; Mutation; Neoplasms; Peptides; Pinocytosis; Protein Conformation; Pyrimidines; Tumor Suppressor Protein p53; Viral Proteins