Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ST1481, a lead compound of a novel potent 7-substituted lipophilic camptothecin series, is able to overcome several mechanisms of drug resistance and was selected for clinical development. This study was designed to examine the antitumor activity of ST1481 in the treatment of preclinical models of human p53-defective hormone-refractory prostate carcinoma (DU145, PC3, and JCA-1) and to explore the cellular bases of the efficacy of camptothecins. A cellular pharmacology study (cytotoxicity, apoptosis, cellular drug accumulation, DNA damage, and cell cycle perturbation) was performed in DU145 and PC3 cells, characterized by a different cell cycle checkpoint status. The introduction of wild-type p53 in PC3 cells appreciably decreased the drug sensitivity. The 7-substituted camptothecins exhibited a high cytotoxic potency that paralleled their relative ability to induce DNA damage and a substantially increased cellular accumulation as compared to topotecan. The cytotoxic effect of camptothecins in DU145 cells was associated with arrest in S phase and early activation of apoptosis, whereas PC3 cells responded to drugs by a persistent block in G2 phase with a cytostatic effect and a late apoptosis. The efficiency of S phase checkpoint in DU145 cells was supported by a time-dependent decrease of DNA synthesis following treatment. In spite of an apparent cytostatic response and apoptosis resistance, the PC3 tumor was more responsive to in vivo treatment with camptothecins than the DU145 model. Indeed, the therapeutic outcome did not reflect the cell susceptibility to early activation of apoptosis. We suggest that cell death in PC3 cells is a delayed event consequent to persistent arrest in G2 and insufficient repair of DNA damage. ST1481 was appreciably more effective than topotecan in all tested tumors. In conclusion, the results indicated a relevant efficacy of camptothecins against human prostate carcinoma models, in spite of p53 alterations. Although p53 status could influence DNA damage and cell cycle checkpoints, p53 mutation was not a determinant of resistance. The results support that, in addition to the extent and persistence of topoisomerase I-mediated DNA damage, cell cycle checkpoints and DNA damage signaling pathways are critical determinants of tumor responsiveness to camptothecins. A role of cell cycle checkpoints activated by DNA damage in cell response is supported by the modulation of transcriptional profile.
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PMID:Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models. 1269 69

The anticancer agent topotecan is considered to be S-phase specific. This implies that cancer cells that are not actively replicating DNA could resist the effects of the drug. The cycle specificity of topotecan action was investigated in MCF-7 cells, using time-lapse microscopy to link the initial cell cycle position during acute exposures to topotecan with the antiproliferative consequences for individual cells. The bioactive dose range (0.5-10 microM) for 1-h topotecan exposures was defined by rapid drug delivery and topoisomerase I trapping. Topotecan caused pan-cycle induction and activation of p53. Lineage analysis of the time-lapse sequences identified cells initially in S-phase and G2, and defined the time to mitosis for cells originating from G2, S-phase and G1. Topotecan prevented all mitoses from S-phase cells and G1 cells (half-maximal effects at 0.14 microM and 0.96 microM, respectively). No dose of topotecan completely prevented mitosis among G2 cells, and at saturating doses of topotecan about half the cells of G2 origin continued dividing (the half-maximal effects was at 0.31 microM). Overall, topotecan differentially targeted G1-, S- and G2-phase cells, but many G2 cells were resistant to topotecan, presenting a clear route for cell cycle-mediated drug resistance.
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PMID:Tracking the cell cycle origins for escape from topotecan action by breast cancer cells. 1269 1

To uncover transcriptional stress responses related to p53, we used cDNA microarrays (National Cancer Institute Oncochips comprising 6500 different genes) to characterize the gene expression profiles of wild-type p53 HCT-116 cells and an isogenic p53 knockout counterpart after treatment with topotecan, a specific topoisomerase I inhibitor. The use of the p53 knockout cells had the advantage over p53-overexpressing systems in that p53 activation is mediated physiologically. RNA was extracted after low (0.1 microM)- and high (1 microM)-dose topotecan at multiple time points within the first 6 h of treatment. To facilitate simultaneous study of the p53 status and pharmacological effects on gene expression, we developed a novel "cross-referenced network" experimental design and used multiple linear least squares fitting to optimize estimates of relative transcript levels in the network of experimental conditions. Approximately 10% of the transcripts were up- or down-regulated in response to topotecan in the p53+/+ cells, whereas only 1% of the transcripts changed in the p53-/- cells, indicating that p53 has a broad effect on the transcriptional response to this stress. Individual transcripts and their relationships were analyzed using clustered image maps and by a novel two-dimensional analysis/visualization, gene expression map, in which each gene expression level is represented as a function of both the genotypic/phenotypic difference (i.e., p53 status) and the treatment effect (i.e., of topotecan dose and time of exposure). Overall, drug-induced p53 activation was associated with a coherent genetic program leading to cell cycle arrest and apoptosis. We identified novel p53-induced and DNA damage-induced genes (the proapoptotic SIVA gene and a set of transforming growth factor beta-related genes). Genes induced independently of p53 included the antiapoptotic cFLIP gene and known stress genes related to the mitogen-activated protein kinase pathway and the Fos/Jun pathway. Genes that were negatively regulated by p53 included members of the antiapoptotic protein chaperone heat shock protein 70 family. Finally, among the p53-dependent genes whose expression was independent of drug treatment was S100A4, a small Ca(2+)-binding protein that has recently been implicated in p53 binding and regulation. The new experimental design and gene expression map analysis introduced here are applicable to a wide range of studies that encompass both treatment effects and genotypic or phenotypic differences.
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PMID:Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic study. 1278 83

Treatment of solid tumors with combinations of chemotherapeutic agents has not led to significant increases in long-term survival. Recent studies support a role for inhibitors of checkpoint arrest as a means to enhance the cytotoxicity of chemotherapy. We have shown previously that triptolide (PG490), an oxygenated diterpene derived from a Chinese medicinal plant, induces apoptosis in cultured tumor cells and sensitizes tumor cells to topoisomerase inhibitors by blocking p53-mediated induction of p21. Here we extend our studies to a tumor xenograft model and evaluate the efficacy and safety of PG490-88 (14-succinyl triptolide sodium salt), a water-soluble prodrug of PG490. We also look at the combination of PG490 or PG490-88 with CPT-11, a topoisomerase I inhibitor, in cultured cells and in the tumor xenograft model. We show that PG490-88 is a safe and potent antitumor agent when used alone, causing tumor regression of lung and colon tumor xenografts. We also show that PG490-88 acts in synergy with CPT-11 to cause tumor regression. A phase I trial of PG490-88 for solid tumors began recently and safety and optimal dosing data should accrue within the next 12 months. Our findings that PG490-88 causes tumor regression and that it acts in synergy with DNA-damaging chemotherapeutic agents suggest a role as an antineoplastic agent and chemosensitizer for the treatment of patients with solid tumors.
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PMID:PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. 1455 4

The tumor suppressor protein p53 and the human DNA topoisomerase I (htopoI) interact with each other, which leads to a stimulation of the catalytic activity of htopoI. Moreover, p53 stimulates the topoisomerase I-induced recombination repair (TIRR) reaction. However, little was known about how p53 stimulates this topoisomerase I activity. Here we demonstrate that monomeric p53 is sufficient for the stimulation of the topoisomerase I-catalyzed relaxation activity, but the tetrameric form of p53 is required for the stimulation of TIRR. We also show that p53 stimulates topoisomerase I activity by increasing the dissociation of htopoI from DNA. Since htopoI forms a closed ring structure around the DNA, our results suggest that p53 induces a conformational change within htopoI that results in an opening of the clamp, and thereby releases htopoI from DNA.
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PMID:p53 stimulates human topoisomerase I activity by modulating its DNA binding. 1460 18

The anticancer drug, 9-nitrocamptothecin (9NC), has demonstrated an unprecedented activity against human caner cells grown in cultures and as xenografts in nude mice. 9NC-induced apoptosis of cancer cells is mediated by the nuclear enzyme, topoisomerase I, and executed by pathways that involve cytochrome c release from the mitochondrion and/or activation of death receptors depending on the cell type. Alternatively, 9NC has exhibited ability to induce differentiation or senescence of certain cell types in vitro. In several instances, the 9NC activities can be regulated by Bcl-2 family proteins and cell cycle-associated proteins, p53, p21 and Cdks. Also, 9NC can inhibit HIV replication in infected T- and monocytic cells in vitro. Development of resistance to 9NC, associated with mutations in the topoisomerase I gene, can be overcome by regulating specific proteins, such as RKIP, other than topoisomerase I. Finally, derivatives (i.e., alkyl esters) of 9NC, liposome-encapsulated 9NC and combined treatment of 9NC with ionizing radiation or hyperthermia are other approaches to enhance the apoptotic activity of 9NC against human cancer cells.
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PMID:Camptothecin and 9-nitrocamptothecin (9NC) as anti-cancer, anti-HIV and cell-differentiation agents. Development of resistance, enhancement of 9NC-induced activities and combination treatments in cell and animal models. 1466 58

Chromosomal translocations and retroviral integration events at breakpoint cluster regions (bcrs) have been associated with leukaemias. To directly compare the effect of different cis-regulatory sequences on recombination, we adapted our SV40 based model system to the analysis of correspondingly selected bcrs from the TAL1, LMO2, retinoic acid receptor alpha (RARalpha) and MLL genes. We show that a 399 bp fragment from the MLL bcr is sufficient to cause a 3-4-fold stimulation of spontaneously occurring DNA exchange and to respond to etoposide by up to 10-fold further elevated frequencies, i.e. to mimic the fragility of the 8.3 kb bcr during chemotherapy. To analyse the regulatory role of p53 in recombination involving leukaemia-related sequences, we stably expressed wtp53 and a transactivation negative mutant. Consistent with the proposed role of p53 as a suppressor of error-prone recombination, both p53 proteins down-regulated recombination with most of the sequences tested, even with the MLL bcr after etoposide treatment. Surprisingly, however, p53 stimulated recombination, in constructs carrying the RARalpha bcr fragment. This is the first study, which provides evidence for a stimulatory role of p53 in homologous recombination. Our data further indicate that inhibition of topoisomerase I can mimic the effects of p53 on stimulating recombination on the RARalpha bcr. Thus, these data also firstly describe a biological role of the biochemical interactions between p53 and topoisomerase I that may have implications for a gain-of-function phenotype of certain p53 mutants in genetic destabilization.
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PMID:Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53. 1474 15

A critical challenge in cancer research is to identify genetic lesions that sensitize patients to chemotherapy. p53, which is mutated in nearly one-third to half of glioblastomas, may be such a lesion. In this paper, we demonstrate that p53 disruption dramatically sensitizes glioblastoma cells to DNA topoisomerase I inhibitor-mediated apoptosis. Using 19 glioblastoma cell lines, including 15 low-passage ex vivo cell lines derived from patients, as well as isogenic glioblastoma cells varying in p53 status, we show that clinically relevant levels of SN-38 potently induce cell cycle arrest and temporary senescence in glioblastoma cells with wild-type p53 while causing massive apoptosis in p53-deficient cells (P<0.0002). We demonstrate that glioblastoma cells with wild-type p53 proliferate when recultured in drug-free medium, whereas p53-deficient cells do not. We also show that p16 protein expression is neither necessary nor sufficient for initiation and/or maintenance of SN-38-induced arrest/senescence. These results indicate that p53 disruption has a dramatic effect on how glioblastoma cells process topoisomerase I inhibitor-mediated DNA damage.
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PMID:p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition. 1496 Oct 77

To elucidate mechanisms of resistance to chemotherapies currently used in the first-line treatment of advanced colorectal cancer, we have developed a panel of HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic colorectal cancer cell lines resistant to the antimetabolite 5-fluorouracil (5-FU), topoisomerase I inhibitor irinotecan (CPT-11), and DNA-damaging agent oxaliplatin. These cell lines were generated by repeated exposure to stepwise increasing concentrations of each drug over a period of several months. We have demonstrated a significant decrease in sensitivity to 5-FU, CPT-11, and oxaliplatin in each respective resistant cell line relative to the parental line as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, with increases in IC(50 (72 h)) concentrations ranging from 3- to 65-fold. Using flow cytometry, we have also demonstrated compromised apoptosis and cell cycle arrest in 5-FU-, oxaliplatin-, and CPT-11-resistant cell lines compared with the parental lines after exposure to each drug. In addition, we found that resistance to 5-FU and oxaliplatin was higher in parental p53(-/-) cells compared with parental p53(+/+) cells, with an approximately 5-fold increase in IC(50 (72 h)) for each drug. In contrast, the IC(50 (72 h)) doses for CPT-11 were identical in the p53 wild-type and null cell lines. Furthermore, apoptosis after treatment with 5-FU and oxaliplatin, but not CPT-11, was significantly reduced in parental p53(-/-) cells compared with parental p53(+/+) cells. These data suggest that p53 may be an important determinant of sensitivity to 5-FU and oxaliplatin but not CPT-11. Using semiquantitative reverse transcription-PCR, we have demonstrated down-regulation of thymidine phosphorylase mRNA in both p53(+/+) and p53(-/-) 5-FU-resistant cells, suggesting that decreased production of 5-FU active metabolites may be an important resistance mechanism in these lines. In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein. In CPT-11-resistant cells, we found reduced mRNA levels of carboxylesterase, the enzyme responsible for converting CPT-11 to its active metabolite SN-38, and topoisomerase I, the SN-38 target enzyme. In addition, we noted overexpression of breast cancer resistance protein in the CPT-11-resistant lines. These cell lines are ideal tools with which to identify novel determinants of drug resistance in both the presence and absence of wild-type p53.
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PMID:Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. 1504 37

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has demonstrated selective cytotoxicity against a number of specific tumor types, a variety of infectious agents such as HIV, malaria and bacteria, and the inflammatory process in general. Biological activity was first demonstrated in melanoma cell lines and was confirmed in mice bearing human melanoma xenografts. These in vivo studies also established a favorable safety margin for betulinic acid, as systemic side effects were not observed at any dose. Recently, considerable in vitro evidence has demonstrated that betulinic acid is effective against small- and non-small-cell lung, ovarian, cervical, and head and neck carcinomas. Published data suggest that betulinic acid induces apoptosis in sensitive cells in a p53- and CD95-independent fashion. While the precise molecular target and mechanism of action remain elusive and are the focus of a number of ongoing research programs, accumulated experimental evidence indicates that betulinic acid functions through a mitochondrial-mediated pathway. Supplemental reports suggest that the generation of reactive oxygen species, inhibition of topoisomerase I, activation of the MAP kinase cascade, inhibition of angiogenesis, and modulation of pro-growth transcriptional activators and aminopeptidase N activity may play a role in betulinic acid-induced apoptosis. These potential mechanisms of action may enable betulinic acid to be effective in cells resistant to other chemotherapeutic agents. Arguments supporting the role of this agent in the treatment of cancers and other infectious conditions will be reviewed.
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PMID:Betulinic acid: a promising anticancer candidate. 1505 42


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