cp-31398 and Neoplasms

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

Topics: Cell Cycle Checkpoints; Histone Deacetylase Inhibitors; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Protein Serine-Threonine Kinases; Pyrimidines; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

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

In the majority of human cancers, the tumor suppressor activity of p53 is impaired because of mutational events or interactions with other proteins (ie, MDM2). The loss of p53 function is responsible for increased aggressiveness of cancers, while tumor chemoresistance and radioresistance are dependent upon the expression of mutant p53 proteins.. Review of the literature indicates that p53 acts primarily as a transcription factor whose function is subject to a complex and diverse array of covalent post-translational modifications that markedly influence the expression of p53 target genes responsible for cellular responses such as growth arrest, senescence, or apoptosis. The ability of p53 to induce apoptosis in cancer cells is believed essential for cancer therapy.. Numerous data indicate that p53 dependent apoptosis is a relevant factor in determining the efficacy of anticancer treatments. Thus, the development of new strategies for restoration of p53 function in human tumors is considered an important issue. Two main approaches for restoration of p53 function have been pursued that impact anticancer treatments: (a) de novo expression of wild-type p53 (wt-p53) through gene therapy and (b) identification of small molecules reactivating wt-p53 function.. The extensive body of knowledge acquired has identified manipulations of p53 signaling as a relevant issue for successful therapies. In this context, the recognition of p53 status in cancer cells is significant and would help considerably in the selection of an appropriate therapeutic approach. p53 manipulations for cancer therapy have revealed the need for specificity of p53 activation and ability to spare body tissues. Furthermore, the promising results obtained by using molecules competent to reactivate wt-p53 functions in cancer cells provide the basis for the design of new molecules with lower side effects and higher anti-tumor efficiency. The reexpression and reactivation of p53 protein in human cancer cells would increase tumor susceptibility to radiation or chemotherapy enhancing the efficacy of standard therapeutic protocols.

Topics: Apoptosis; DNA Damage; Genes, p53; Genetic Therapy; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Receptors, Death Domain; Transcription, Genetic; Tumor Suppressor Protein p53

The p53 tumor suppressor gene is mutated in around 50% of all human tumors. Most mutations inactivate p53's specific DNA binding, resulting in failure to activate transcription of p53 target genes. As a consequence, mutant p53 is unable to trigger a p53-dependent biological response, that is cell cycle arrest and apoptosis. Many tumors express high levels of nonfunctional mutant p53. Several strategies for restoration of wild-type p53 function in tumors have been designed. Wild-type p53 reconstitution by adenovirus-mediated gene transfer has shown antitumor efficacy in clinical trials. Screening of chemical libraries has allowed identification of small molecules that reactivate mutant p53 and trigger mutant p53-dependent apoptosis. These novel strategies raise hopes for more efficient cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Defective Viruses; DNA, Neoplasm; Drug Delivery Systems; Gene Expression Regulation, Neoplastic; Genes, p53; Genetic Therapy; Genetic Vectors; Humans; Mastadenovirus; Mice; Mutation; Neoplasm Proteins; Neoplasms; Neoplastic Syndromes, Hereditary; Peptide Fragments; Protein Binding; Pyrimidines; Transcription, Genetic; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

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

A sensitive and accurate approach for the determination of CP-31398 (N-{2-[(E)-2-(4-methoxy-phenyl)-vinyl]-quinazolin-4-yl}-N',N'-dimethyl-propane-1,3-diamine hydrochloride) in rat and dog plasma by LC-MS/MS was validated to support preclinical toxicological and pharmacological studies. Based on the results of stability experiments with diluted CP-31398 solutions using NMR, LC-MS/MS and LC-Q-TOF, all sample preparation and handling steps were performed under yellow light to avoid CP-31398 decomposition. CP-31398 was extracted by protein precipitation with acetonitrile and separated using a Phenomenex Luna 3μm phenyl-hexyl, 100Å, 30×2.0mm column (rat plasma) or a Phenomenex Synergi 4μ Polar-RP, 80Å, 30×2.0mm column (dog plasma) at a flow rate of 0.30mL/min. The mobile phase consisted of A: 1% formic acid in water and B: 1% formic acid in methanol or acetonitrile. Total run times for rat and dog samples were 7 and 8min, respectively, with accompanying retention times of 1.8 for both columns. A turbo ion spray interface was used as the ion source operating in positive mode. Calibration curves were linear from 5 to 1000ng/mL. Linearity was assessed using the external standard method. Within-run and between-run accuracy was 93-109% of the true value for all analytes with precision (SD) of 8% or less for all experiments. The validated method was applied to preclinical toxicology studies in rats and dogs after oral administration of CP-31398.

Topics: Animals; Antineoplastic Agents; Chemoprevention; Chromatography, Liquid; Dogs; Drug Evaluation, Preclinical; Drug Stability; Female; Light; Male; Neoplasms; Pyrimidines; Rats; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry

Topics: Animals; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Genes, p53; Genetic Engineering; Humans; Imidazolines; Mice; Mutation; Neoplasm Transplantation; Neoplasms; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Tumor Suppressor Protein p53

CP-31398 activates wild-type p53 by a novel mechanism that does not involve phosphorylation of the amino-terminus of p53 and disassociation of MDM2. To identify more potent CP-31398-like p53 activators, we synthesized 4 acridine derivatives with a similar structure to CP-31398. These four compounds induced strong p53 transcription in cells with wild-type p53. We also found that several randomly chosen acridine derivatives, including 9-aminoacridine, amsacrine, quinacrine and acridine orange, induced p53 transcriptional activity. All these acridine derivatives stabilized p53 protein by blocking its ubiquitination, without phosphorylation of ser15 or ser20 on p53. Furthermore, acridine derivatives induced p53-dependent cell death. Knockout of Bax, a p53 target and a key cell death inducer in both intrinsic and extrinsic apoptotic pathways, blocked acridine derivatives from inducing cell death. In addition, in vivo delivery of quinacrine and amsacrine induced p53 transcriptional activity in tumor xenografts. Our results reveal that DNA-intercalating acridine derivatives can induce p53 stabilization by a manner similar to CP-31398. These findings provide insights into p53 regulation in response to DNA intercalating drugs and may assist new anti-cancer drug design.

Topics: Acridines; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Drug Design; Humans; Intercalating Agents; Mice; Mice, Nude; Neoplasms; Pyrimidines; Quinacrine; Transcription, Genetic; Tumor Suppressor Protein p53; Ubiquitin; Xenograft Model Antitumor Assays

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

p53 is considered the guardian of the genome and has a number of biological functions, including cell cycle arrest, DNA repair, and apoptosis. In a recent study by Foster and colleagues, the pharmacological compound CP-31398 was found to stabilize wild-type p53 to enhance its transcriptional activity and inhibit tumor growth in mice. We hypothesize that CP-31398 induces apoptosis by stabilizing the p53 protein and activating the mitochondrial-mediated pathway. Using the wild-type p53 HCT116+/+ and the p53-deficient HCT116-/- colon carcinoma cell lines, we demonstrate here that CP-31398 induces apoptosis in a dose-, time-, and p53-dependent manner. CP-31398 dramatically elevated p53 and p21(Waf1) protein levels in HCT116+/+, while a smaller p53-independent p21(Waf1) induction by CP-31398 in HCT116-/- cells was also observed. Moreover, we also found that CP-31398 increased Bax expression, altered mitochondrial membrane potential causing the release of cytochrome c, and induced the cleavage of caspases-9 and -3. Taken together, our results indicate that CP-31398 induces p53-dependent apoptosis by activating the Bax/mitochondrial/caspase-9 pathway. Elucidating the mechanism by which CP-31398 induces cell death may establish it as an anticancer agent.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma; Caspase 3; Caspase 9; Caspases; Cell Division; Cell Transformation, Neoplastic; Colonic Neoplasms; Cytochrome c Group; Eukaryotic Cells; Humans; Membrane Potentials; Mitochondria; Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Tumor Cells, Cultured; Tumor Suppressor Protein p53