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)

The RRR-alpha-tocopheryl succinate derivative of vitamin E, referred to as vitamin E succinate (VES), inhibits the proliferation of three metastatic human prostatic cancer cell lines, LNCaP, PC-3, and DU-145. LNCaP is a lymph node-derived androgen-sensitive prostate cell line; these cells are defective for response to transforming growth factor-beta (TGF-beta) but are normal for cell cycle-related tumor suppressor genes: p53 and retinoblastoma (Rb). PC-3 is a bone marrow-derived androgen-insensitive prostate cell line; these cells are defective for both p53 alleles but normal for both Rb alleles. DU-145 is a brain-derived androgen-insensitive prostate cell line; these cells are defective for both p53 and both Rb alleles. VES at 5, 10, and 20 micrograms/ml inhibited DNA synthesis in the three cell lines in a dose-dependent manner. Purified TGF-beta 1 at 1 ng/ml inhibited DNA synthesis of PC-3 cells within 24-72 hours and DU-145 cells at 72 hours but did not inhibit DNA synthesis of LNCaP cells. Previous studies in our laboratory showed that VES growth-inhibited tumor cells secrete biologically active antiproliferative factor TGF-beta s, suggesting that VES's mechanism of growth inhibition may involve the TGF-beta system of growth control.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. 858 52

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
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PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.
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PMID:Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta. 935 86

The teratogenicity of many xenobiotics is thought to depend at least in part upon their bioactivation by embryonic cytochromes P450, prostaglandin H synthase (PHS) and lipoxygenases (LPOs) to electrophilic and/or free radical reactive intermediates that covalently bind to or oxidize cellular macromolecules such as DNA, protein and lipid, resulting in in utero death or teratogenesis. Using as models the tobacco carcinogens benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the anticonvulsant drug phenytoin, structurally related anticonvulsants (e.g. mephenytoin, nirvanol, trimethadione, dimethadione) and the sedative drug thalidomide, we have examined the potential teratologic relevance of free radical-initiated, reactive oxygen species (ROS)-mediated oxidative molecular target damage, genotoxicity (micronucleus formation) and DNA repair in mouse and rabbit models in vivo and in embryo culture, and in vitro using purified enzymes or cultured rat skin fibroblasts. These teratogens were bioactivated by PHS and LPOs to free radical reactive intermediary metabolites, characterized by electron spin resonance spectrometry, that initiated ROS formation, including hydroxyl radicals, which were characterized by salicylate hydroxylation. ROS-initiated oxidation of DNA (8-hydroxy-2'-deoxyguanosine formation), protein (carbonyl formation), glutathione (GSH) and lipid (peroxidation), and embryotoxicity were shown for phenytoin, its major hydroxylated metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin [HPPH], thalidomide, B[a]P and NNK in vivo and/or in embryo culture, the latter indicating a teratologically critical role for embryonic, as distinct from maternal, processes. DNA oxidation and teratogenicity of phenytoin and thalidomide were reduced by PHS inhibitors. Oxidative macromolecular lesions and teratogenicity also were reduced by the free radical trapping agent phenylbutylnitrone (PBN), and the antioxidants caffeic acid and vitamin E. In embryo culture, addition of superoxide dismutase (SOD) to the medium enhanced embryonic SOD activity, and SOD or catalase blocked the oxidative lesions and embryotoxicity initiated by phenytoin and B[a]P, suggesting a major contribution of ROS, as distinct from covalent binding, to the teratologic mechanism. In in vivo studies, other antioxidative enzymes like GSH peroxidase, GSH reductase and glucose-6-phosphate dehydrogenase (G6PD) were similarly protective. Even untreated G6PD-deficient mice had enhanced embryopathies, indicating a teratological role for endogenous oxidative stress. In cultured fibroblasts, B[a]P, NNK, phenytoin and HPPH initiated DNA oxidation and micronucleus formation, which were inhibited by SOD. Oxidation of DNA may be particularly critical, since transgenic mice with +/- or -/- deficiencies in the p53 tumor suppressor gene, which facilitates DNA repair, are more susceptible to phenytoin and B[a]P teratogenicity. Even p53-deficient mice treated only with normal saline showed enhanced embryopathies, suggesting the teratological importance of endogenous oxidative stress, as observed with G6PD deficiency. These results suggest that oxidative macromolecular damage may play a role in the teratologic mechanism of xenobiotics that are bioactivated to a reactive intermediate, as well in the mechanism of embryopathies occurring in the absence of xenobiotic exposure.
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PMID:Oxidative damage in chemical teratogenesis. 943 60

The biological effects of antioxidants are often considered in terms of their effects on oxygen or lipid radicals. However, antioxidants can also exert their effects through altering the cellular redox potential. Herein, we report that sulfur-containing antioxidants such as N-acetylcysteine and dimercaptopropanol induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells. In contrast, chain-breaking antioxidants such as vitamin E lacked this activity. An increased glutathione level was not required for apoptosis; however, all apoptosis-inducing antioxidants elevated the total cellular thiol levels. Antioxidant-induced apoptosis required the p53 tumor suppressor gene. N-Acetylcysteine elevated p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation rather than by altering the protein stability. The p53 induction occurred in normal cells. These observations indicate a redox sensor for p53 induction in vivo, with additional transformation-specific information being required for apoptosis. Manipulating p53-dependent apoptosis with nontoxic antioxidants may have a direct clinical application.
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PMID:Antioxidant action via p53-mediated apoptosis. 956 90

The hybrid gene BCR-ABL that typifies chronic myeloid leukemia (CML) represents an attractive target for therapy with antisense oligodeoxyribonucleotides (ODN). A central obstacle in the therapeutic application of ODN is their poor cellular uptake. Adding various lipophilic conjugates to the ODN backbone has been reported to improve uptake, and electroporation of target cells has also been shown to enhance intracellular ODN delivery. We have shown that (1) BCR-ABL-directed ODN will specifically decrease the level of BCR-ABL mRNA, provided that cells are first permeabilized with Streptolysin-O (SL-O), and (2) chimeric methylphosphonodiester:phosphodiester ODN directed against 9 bases either side of the BCR-ABL junction are more efficient ODN effectors than structures composed solely of phosphodiester or phosphorothioate linkages. In this study, we compared the efficacy of lipophilic conjugation, SL-O permeabilization and electroporation on the intracellular delivery and molecular effect of BCR-ABL-directed ODN. b2a2- and b3a2-directed chimeric ODN were synthesized either unmodified or with one of the following groups at the 5' end: cholesterol, vitamin E, polyethylene glycol of average molecular weight 2,000 or 5,000, N-octyl-oligo-oxyethylene, or dodecanol. ODN associated with Lipofectin was also studied. Comparison was made in untreated, electroporated, and SL-O permeabilized KYO1 cells. Uptake was examined by fluorescence microscopy and flow cytometry, using ODN structures that were 3' labeled with fluorescein. The effect on target BCR-ABL mRNA expression was analyzed by Northern blotting. Several conjugated structures associated avidly with the cell membrane without achieving significant intracellular uptake or molecular effect. Similarly, ODN:Lipofectin complexes moderately increased cell association, without enhancing intracellular levels of ODN or inducing detectable molecular effect. In SL-O permeabilized or electroporated cells, uptake was approximately 1 to 2 logs greater than in untreated cells, and rapid nuclear localization was seen, especially with unmodified chimeric ODN. In SL-O permeabilized cells treated with ODN directed to the b2a2 and b3a2 junctions respectively, b2a2 BCR-ABL mRNA levels at 4 hours were reduced to 2. 6% +/- 2.1% and 38.4% +/- 1.3% of control values. In cells permeabilized by electroporation, BCR-ABL mRNA levels were decreased to 4.0% +/- 1.4% of control levels by b2a2 directed ODN, although very little nontargeted suppression was seen with b3a2-targeted ODN (93.4% +/- 4.2% of control). Greater cell to cell variation in ODN uptake was seen for SL-O permeabilized cells when compared with electroporated cells, suggesting that, after SL-O permeabilization, relatively unpermeabilized and overpermeabilized populations may coexist. No structure had any effect on the level of irrelevant (p53, MYC, and GADPH) mRNA levels. We conclude that the conjugation of chimeric ODN with one of the above-mentioned lipophilic groups or the complexing of ODN with Liopfectin does not improve either intracellular delivery of ODN or the molecular effect. In contrast, both electroporation and SL-O permeabilization (1) considerably enhanced uptake of chimeric ODN (even for structures without a conjugate group) and (2) achieved significant suppression of target mRNA levels.
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PMID:Improving the intracellular delivery and molecular efficacy of antisense oligonucleotides in chronic myeloid leukemia cells: a comparison of streptolysin-O permeabilization, electroporation, and lipophilic conjugation. 961 72

Despite the benefits of sunscreens, ultraviolet (UV) exposure can still lead to skin cancer. In this study we investigated the effect of topical application of the antioxidant vitamin E acetate (VEA) on the inhibition of UV-induced carcinogenesis. Hairless SKH-1 mice received 5.2 mg of VEA 30 min before (VEA/UV) or after (UV/ VEA) a single minimal erythemic dose of UV light. Vehicle-control animals received acetone 30 min before UV exposure (Ace/UV). After 24 h, cyclobutane dimer repair was twofold and 1.5-fold greater in the UVNEA and VEA/UV groups, respectively. Expression of p53 protein in the UV/VEA group was maximum at 12 h after UV exposure, whereas in the Ace/UV- and VEA/UV-treated mice, maximum p53 immunostaining was statistically higher at 15 h (P = 0.03). DNA synthesis as determined by 5-bromo-2'-deoxyuridine incorporation was twofold higher after 15 h in all groups but was not statistically different among treatment groups. Protein levels of cyclin D1 and p21 were increased in both VEA groups by 6 h. In addition, VEA treatments delayed tumor formation and yield for the first 20 wk, although this difference was lost by 30 wk. The telomerase activity of carcinomas from the UV/VEA-treated mice was statistically lower than that of the Ace/UV-treated mice (P = 0.05). This study showed that although VEA may mitigate some of the initial events associated with UV irradiation such as DNA damage and p53 expression, it has limited potential in preventing UV-induced proliferation and tumor formation.
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PMID:The effect of vitamin E acetate on ultraviolet-induced mouse skin carcinogenesis. 983 78

Lung cancer remains the leading cause of cancer death in the United States and is one of the world's leading causes of preventable death. Technologic advances have brought new modalities that may be useful for the early detection of lung cancer. However, because of the large number of persons at increased risk for lung cancer, screening is a formidable task. There are several risk factors that can be identified, including potential susceptibility factors, which may aid in pinpointing individuals who need to participate in regular screening programs. Aside from recognized environmental exposures including cigarette smoking, there are a number of genetic and metabolic susceptibility factors that have been examined. These include polymorphisms in the cytochrome p450 enzymes and the metabolizing capability of glutathione s-transferase or acetylation. Additionally, defects in DNA repair and in bleomycin sensitivity assays may also aid in identifying individuals who are at an increased risk for lung cancer. Additional work has been done in the area of characterizing the molecular alterations in the bronchial epithelium in high-risk smokers. This manuscript addresses only selected molecular alterations that have been examined in preneoplastic bronchial epithelium. In addition to mutations in the k-ras oncogene and the p53 gene, which are frequently seen in malignancy, alterations in the p16 gene, microsatellite instability and loss of heterozygocity are also promising potential markers of preneoplasia. The hnRNP A2/B1 gene also shows some promising increased expression in preneoplasia. Lung cancer prevention has made some strides. A number of trials with molecular and morphologic intermediate endpoints have been conducted and have suggested that some of the molecular alterations and morphologic alterations are reversible. However, the rate of spontaneous regression of these lesions is, as yet, uncharacterized. Two recent large studies, the beta-carotene and retinol efficacy trial (CARET) trial conducted in the United States and the Alpha-Tocopherol Beta Carotene (ATBC) trial conducted in Finland, both demonstrated an unexpected increased risk for lung cancer associated with beta-carotene supplementation. The EUROSCAN trial evaluation of vitamin A and N-acetylcystine also showed no benefit to supplementation in reducing risk for lung cancer. Results from the Intergroup study of 1 3-cis-retinoic acid are pending, and plans are underway for an Intergroup trial studying high selenium yeast to reduce lung cancer risk. Hopefully, the combination of identifying markers of increased risk among the numerous current and former smokers will identify high-risk populations to participate in future trials of promising agents that may lead to reduction in incidence and mortality of the leading cause of cancer death.
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PMID:Early detection and prevention of lung cancer. 1075 Jul 26

Epidemiological evidence has suggested an association between diets rich in antioxidants and diminished risks of various types of cancer. Proposed mechanisms for protective effects of antioxidants have involved inhibition of free radical-mediated DNA damage. Recent data suggest that antioxidants may prevent or eliminate cancerous cells through their ability to inhibit proliferation or to induce programmed cell death (PCD). To begin to identify cell cycle and cell death regulatory factors involved in antioxidant-induced growth arrest and PCD, we have studied colorectal carcinoma cells (CRCs) that differ in expression of the tumor suppressor protein p53, and of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). The antioxidants, N-acetylcysteine (NAC) and vitamin E either inhibited proliferation in a p53-independent manner without affecting cell viability or induced cell death. Growth arrest was not associated with upregulation of the CDK inhibitors p21(Waf1/Cip1), p18(ink4c) or p16(ink4a), but was associated with a decrease in reactive oxygen species (ROS). In contrast to previous observations, the absence of p21(Waf1/Cip1) increased susceptibility of CRCs to antioxidant-induced PCD. NAC decreased levels of retinoblastoma protein (Rb) phosphorylation in all cells tested, but Rb was cleaved only in cells which underwent NAC-induced death. Although NAC decreased ROS in all cells studied, cell lines in which PCD occurred had higher baseline levels of ROS than cell lines in which proliferation was blocked. These observations suggest that expression of p21(Waf1/Cip1) and basal levels of ROS are important determinants of outcome after antioxidant treatment.
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PMID:p53-independent inhibition of proliferation and p21(WAF1/Cip1)-modulated induction of cell death by the antioxidants N-acetylcysteine and vitamin E. 1093 2

Peripheral neuropathy following cisplatin treatment is a major limiting factor in cisplatin chemotherapy of cancer patients. We investigated the pathomechanism underlying cisplatin neuropathy using a mouse dorsal root ganglion neuron-neuroblastoma hybrid cell line (N18D3) developed in our laboratory. DNA fragmentation, a characteristic feature of apoptosis, was induced in hybrid neurons following treatment with cisplatin. Accumulation of p53, Fas, and Fas ligand (Fas-L) was also demonstrated in these neurons. Preincubation with N-acetylcysteine (NAC), a precursor of glutathione, blocked cisplatin-induced apoptosis completely, whereas Trolox, a vitamin E analogue, blocked it partially. Cisplatin-induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In contrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin-induced Fas/Fas-L accumulation. These results suggest that the neuroprotective effects of antioxidants against cisplatin-induced neurotoxicity in hybrid neurons are mediated mainly through the inhibition of p53 accumulation but not of Fas/Fas-L accumulation by these antioxidants.
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PMID:Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand. 1093 75


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