Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several recently identified intracellular proteins associate with the tumor necrosis factor (TNF) receptor and activate nuclear transcription factor (NF)-kappaB, c-Jun kinase, and apoptosis. However, the mechanism is not understood. In the present report, we investigated the role of reactive oxygen intermediates in TNF-induced signaling. Overexpression of manganese superoxide dismutase (Mn-SOD) in human breast cancer MCF-7 cells completely abolished TNF-mediated NF-kappaB activation, IkappaB alpha degradation, p65 nuclear translocation, and NF-kappaB-dependent reporter gene expression. Besides TNF, phorbol ester-, okadaic acid-, ceramide-, and lipopolysaccharide-induced activation of NF-kappaB was blocked by Mn-SOD, indicating a common pathway of activation. H2O2-induced NF-kappaB activation, however, was potentiated. In addition, Mn-SOD blocked the TNF-mediated activation of activated protein-1, stress-activated c-Jun protein kinase, and mitogen-activated protein kinase kinase. TNF-induced antiproliferative effects and caspase-3 activation, indicators of apoptosis, were also completely suppressed by transfection of cells with Mn-SOD. Suppression of apoptosis induced by okadaic acid, H2O2, and taxol was also inhibited by Mn-SOD but not that induced by vincristine, vinblastine, or daunomycin. Overall, these results demonstrate that, in addition to several recently identified signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-kappaB, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.
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PMID:Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. 958 69

Reactive oxygen species (ROS) are involved in a number of disease states where they are believed to be responsible for cellular damage. In this study we examined the effect of ROS generation on polyamine catabolism. Treatment of human breast cancer cells with either H2O2 or hyperoxia increased the activity of spermidine/spermine N1-acetyltransferase (SSAT). These increases occurred before any significant signs of cellular injury. Agents known to decrease the production of reactive oxygen species such as dimethylthiourea and o-phenanthroline prevented the increase in SSAT activity indicating ROS involvement in the induction process. These results suggest that induction of SSAT may be a protective response to oxidative stress in mammalian cells facilitating removal of polyamines from the cell to prevent their toxic accumulation.
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PMID:Induction of spermidine/spermine N1-acetyltransferase in human cancer cells in response to increased production of reactive oxygen species. 960 36

Drug design targeted at microtubules has led to the advent of some potent anti-cancer drugs. In the present study, we demonstrated that microtubule-binding agents (MBAs) taxol and colchicine induced immediate early gene (c-jun and ATF3) expression, cell cycle arrest, and apoptosis in the human breast cancer cell line MCF-7. To elucidate the signal transduction pathways that mediate such biological activities of MBAs, we studied the involvement of mitogen-activated protein (MAP) kinases. Treatment with taxol, colchicine, or other MBAs (vincristine, podophyllotoxin, nocodazole) stimulated the activity of c-jun N-terminal kinase 1 (JNK1) in MCF-7 cells. In contrast, p38 was activated only by taxol and none of the MBAs changed the activity of extracellular signal-regulated protein kinase 2 (ERK2). Activation of JNK1 or p38 by MBAs occurred subsequent to the morphological changes in the microtubule cytoskeleton induced by these compounds. Furthermore, baccatine III and beta-lumicolchicine, inactive analogs of taxol and colchicine, respectively, did not activate JNKI or p38. These results suggest that interactions between microtubules and MBAs are essential for the activation of these kinases. Pretreatment with the antioxidants N-acetyl-L-cysteine (NAC), ascorbic acid or vitamin E, blocked H2O2- or doxorubicin-induced JNKI activity, but had no effect on JNKI activation by MBAs, excluding a role for oxidative stress. However, BAPTA/AM, a specific intracellular Ca2+ chelator, attenuated JNK1 activation by taxol but not by colchicine, and had no effect on microtubule changes induced by taxol. Thus, stabilization or depolymerization of microtubules may regulate JNK1 activity via distinct downstream signaling pathways. The differential activation of MAP kinases opens up a new avenue for addressing the mechanism of action of antimicrotubule drugs.
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PMID:Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. 992 94

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.
Breast Cancer Res Treat 1999 Jun
PMID:Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper. 1051 67

Reactive oxygen metabolites (ROMs), including superoxide anion (O2*-), hydrogen peroxide (H2O2) and hydroxyl radical (*OH), play an important role in carcinogenesis. There are some primary antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which protect against cellular and molecular damage caused by the ROMs. We conducted the present study to determine the rate of O2*- and H2O2 production, and concentration of malondialdehyde (MDA), as an index of lipid peroxidation, along with the SOD, GPx and CAT activities in 54 breast cancer (BC) patients. Forty-two age- and sex-matched patients with minor surgical problems, who had no history of any neoplastic or breast disorders, were taken as controls. The rate of O2*- production was significantly higher (p < 0.001) in BC patients than controls, irrespective of clinical stages and menopausal status. Similarly, H2O2 production was significantly higher in BC patients, especially in stage III and postmenopausal groups, as compared to the respective controls. MDA concentration was also observed significantly elevated in stage II (p < 0.001), stage III (p < 0.01), postmenopausal (p < 0.005), and premenopausal (p < 0.02) group as compared to their corresponding controls. SOD and GPx activities were found significantly raised in all the groups (p < 0.001), except the GPx activity was found a smaller alteration in stage IV (p < 0.02). On the contrary, CAT activity was found significantly depressed in all the study groups. The maximum depression was observed in stage II (-61.8%). Lower CAT activity in our study may be the effect of higher production of ROMs, particularly O2*- and *OH. SOD and GPx, however, were less effected by these higher ROMs production. The results of our study have shown a higher ROMs production and decreased CAT activity, which support the oxidative stress hypothesis in carcinogenesis. The relatively higher SOD and GPx may be due to the response of increased ROMs production in the blood. However, the higher SOD and GPx activities may be inadequate to detoxify high levels of H2O2 into H2O leading to the formation of the most dangerous *OH radical followed by MDA. Therefore, administration of CAT may be helpful in the management of BC patients. However, further elaborate clinical studies are required to evaluate the role of such antioxidant enzymes in BC management.
Breast Cancer Res Treat 2000 Jan
PMID:Lipid peroxidation, free radical production and antioxidant status in breast cancer. 1081 51

The anticancer activity of the hormonal form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], is associated with inhibition of cell cycle progression, induction of differentiation, and apoptosis. In addition, 1,25(OH)2D3 augments the activity of anticancer agents that induce excessive reactive oxygen species generation in their target cells. This study aimed to find out whether 1,25(OH)2D3, acting as a single agent, is a prooxidant in cancer cells. The ratio between oxidized and reduced glulathione and the oxidation-dependent inactivation of glyceraldehyde-3phosphate dehydrogenase (GAPDH) are considered independent markers of cellular reactive oxygen species homeostasis and redox state. Treatment of MCF-7 breast cancer cells with 1,25(OH)2D3 (10-100 nM for 24-48 h) brought about a maximal increase of 41+/-13% (mean +/- SE) in the oxidized/reduced glutathione ratio without affecting total glutathione levels. The in situ activity of glutathione peroxidase and catalase were not affected by 1,25(OH)2D3, as assessed by the rate of H2O2 degradation by MCF-7 cell cultures. Neither did treatment with 1,25(OH)2D3 affect the levels of glutathione reductase or glutathione S-transferase as assayed in cell extracts. The hormone did not affect overall glutathione consumption and efflux as reflected in the rate of decline of total cellular glutathione after inhibition of its synthesis by buthionine sulfoximine. The extent of reversible oxidation-dependent inactivation of GAPDH in situ was determined by comparing the enzyme activity before and after reduction of cell extracts with DTT. The oxidized fraction was 0.13+/-0.02 of total GAPDH in control cultures and increased by 56+/-5.3% after treatment with 1,25(OH)2D3, which did not affect the total reduced enzyme activity. Treatment with 1,25(OH)2D3 resulted in a approximately 40% increase in glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the generation of NADPH. This enzyme is induced in response to various modes of oxidative challenge in mammalian cells. Taken together, these findings indicate that 1,25(OH)2D3 causes an increase in the overall cellular redox potential that could translate into modulation of redox-sensitive enzymes and transcription factors that regulate cell cycle progression, differentiation, and apoptosis.
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PMID:Vitamin D is a prooxidant in breast cancer cells. 1124 48

beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.
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PMID:[Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use]. 1147 85

The peroxiredoxins (Prx) are a family of 25 kDa peroxidases that can reduce H2O2 using an electron from thioredoxin (Trx) or other substances. The mammalian Prx family is divided into six groups (Prx I-VI) on the basis of homology of amino acid sequences. They are located in the cytosol and play a role in the cell signaling system. Previous reports have shown that Prx II has proliferative and anti-apoptotic properties and thus may induce carcinogenic changes. We conducted this study to reveal the change in expression of Prx in human breast cancer in comparison to normal tissues. Western immunoblotting using Prx type I, II and III antibodies was undertaken on 24 human breast cancer tissues and normal counterparts. We used antibodies against purified recombinant NKEF-A/PAG, NKEF-B and MER 5 which are the Prx isoforms. Type I Prx was overexpressed in the cancer tissues of 21 patients (87.5%), type II in 18 patients (75%) and type III in 19 patients (79.2%) in relation to normal tissue. However, no significant relationship was found between Prx overexpression and clinicopathological parameters of breast cancer such as tumor size, lymphatic invasiveness, hormone receptor status or nuclear and histologic grade. In conclusion, Prx is overexpressed in breast cancer tissues to a great extent suggesting that Prx has a proliferative effect and may be related to cancer development or progression.
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PMID:Overexpression of peroxiredoxin in human breast cancer. 1149 2

The mammalian thioredoxins are a family of small redox proteins that undergo NADPH dependent reduction by thioredoxin reductase. Reduced thioredoxins reduce oxidized cysteine groups on proteins including transcription factors to increase their binding to DNA, and is a source of reducing equivalents for enzymes such as thioredoxin peroxidase which removes H2O2 and alkyl peroxides. Thioredoxin-1 is over expressed in many human tumors where it is associated with aggressive tumor growth, inhibited apoptosis and decreased patient survival. Transfection of cells with thioredoxin-1 has been shown to increase cell growth and inhibit apoptosis. We have used DNA micro array to investigate the effects of thioredoxin-1 transfection on the expression of a panel of 520 redox, apoptosis and cell growth related genes in MCF-7 human breast cancer cells. One of the genes whose expression was increased as a result of thioredoxin-1 over expression was thioredoxin peroxidase-2. This increase was confirmed by Northern blotting. Transfection of mouse WEHI7.2 thymoma cells with human thioredoxin peroxidase-2 was found to protect the cells from apoptosis induced by H2O2 but not from apoptosis induced by dexamethasone, doxorubicin or etoposide. Thus, increased thioredoxin peroxidase-2 expression does not explain the widespread antiapoptotic effects of thioredoxin-1.
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PMID:DNA microarray reveals increased expression of thioredoxin peroxidase in thioredoxin-1 transfected cells and its functional consequences. 1176 30

We are studying the induction and repair of DNA damage in lymphocytes of women from families with familial breast cancer and a heterozygous mutation in the breast cancer susceptibility genes BRCA1 or BRCA2. Besides various other functions, BRCA proteins seem to be involved in DNA repair processes like transcription-coupled and double-strand break (dsb) repair. Our previous results indicated a close relationship between the presence of a BRCA1 mutation and sensitivity for the induction of micronuclei (MN) by gamma irradiation and hydrogen peroxide (H2O2). In contrast to the results with the micronucleus assay, we found no significant individual difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the alkaline comet assay. We now investigated further cases heterozygous for a BRCA1 mutation and cases heterozygous for a BRCA2 mutation and show that enhanced micronucleus formation after gamma irradiation and H2O2-treatment is also a feature of lymphocytes carrying a BRCA2 mutation. Investigations with the comet assay did not reveal clear differences with regard to the induction of DNA damage on the individual level. There were also no significant differences between blood samples carrying a BRCA1 or BRCA2 mutation and blood samples from normal controls when the repair capacities (i.e. the kinetics of the removal of radiation-induced DNA effects in the comet assay) were compared. Our results indicate that mutagen sensitivity of lymphocytes heterozygous for a BRCA2 mutation is similar to that of cells with a BRCA1 mutation and BRCA1 and BRCA2 cannot be differentiated at present with the micronucleus test (MNT) or the comet assay.
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PMID:Mutagen sensitivity of peripheral blood from women carrying a BRCA1 or BRCA2 mutation. 1189 Sep 37


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