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)

Evidence from a number of studies suggests that the mechanism by which tumor necrosis factor (TNF) kills transformed cells involves oxidative stress. NAD(P)H:(quinone acceptor) oxidoreductase (NQO1) is an antioxidant enzyme with particular relevance to cancer. The MCF-7 breast cancer cell line was stably transfected with rat NQO1 cDNA to determine whether increased NQO1 activity alters sensitivity to TNF-induced apoptosis. Five clones, with a range of NQO1 enzyme activities from 5- to 50-fold greater than the MCF-7 line, and two control transfectants were examined. Northern blot hybridization analyses and reverse transcription-PCR demonstrated that the increase in NQO1 activity in the transfectants was attributable to expression from the transfected rat sequence. Based on sulforhodamine B assays for the number of viable cells, the NQO1 clones showed increased sensitivity to EO9, an indoloquinone that undergoes bioactive reduction by NQO1. Viability studies also demonstrated that the NQO1 transfectants were significantly more sensitive to TNF than the control transfectants or MCF-7 parent. This increased sensitivity could not be explained by changes in superoxide dismutase or catalase activity or to increased sensitivity to oxidative stress in general, as assessed by response to hydrogen peroxide and paraquat treatment. Using dichlorodihydrofluorescein diacetate as a probe, we found that the NQO1 transfectants had no difference in baseline level of oxidative stress compared to the control cells but did exhibit greater intracellular oxidative stress after TNF treatment. We conclude that NQO1 can affect the TNF-mediated pathway to apoptosis.
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PMID:Increased tumor necrosis factor-alpha sensitivity of MCF-7 cells transfected with NAD(P)H:quinone reductase. 1091 79

Epidemiological evidence links alcohol intake with increased risk in breast cancer. Not all the characteristics of the correlation can be explained in terms of changes in hormonal factors. In this work, we explore the possibility that alcohol were activated to acetaldehyde and free radicals in situ by xanthine dehydrogenase (XDh) and xanthine oxidase (XO) and/or aldehyde oxidase (AO). Incubation of cytosolic fraction with xanthine oxidoreductase (XDh+XO) (XOR) cosubstrates (e.g. NAD+, hypoxanthine, xanthine, caffeine, theobromine, theophylline or 1,7-dimethylxanthine) significantly enhanced the biotransformation of ethanol to acetaldehyde. The process was inhibited by allopurinol and not by pyrazole or benzoate or desferrioxamine and was not accompanied by detectable formation of 1HEt. However, hydroxylated aromatic derivatives of PBN were detected, suggesting either that hydroxyl free radicals might be formed or that XOR might catalyze aromatic hydroxylation of PBN. No bioactivation of ethanol to acetaldehyde was detectable when a cosubstrate of AO such as N-methylnicotinamide was included in cytosolic incubation mixtures. Results suggest that bioactivation of ethanol in situ to a carcinogen, such as acetaldehyde, and potentially to free radicals, might be involved in alcohol breast cancer induction. This might be the case, particularly also in cases of a high consumption of purine-rich food (e.g. meat) or beverages or soft drinks containing caffeine.
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PMID:Cytosolic xanthine oxidoreductase mediated bioactivation of ethanol to acetaldehyde and free radicals in rat breast tissue. Its potential role in alcohol-promoted mammary cancer. 1124 19

The rat form of DT-diaphorase (NAD(P)H: quinone acceptor oxidoreductase; EC 1.6.99.2) is more effective than the human form in activating prodrugs such as CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide). Our site-directed mutagenesis study has revealed that residue 104 (Tyr in the rat enzyme and Gln in the human enzyme) is an important residue responsible for the catalytic differences between the rat and the human enzymes in the activation of CB 1954 (S. Chen et al., 1997, J. Biol. Chem. 272, 1437-1439). The human mutant Q104Y is capable of reducing CB 1954 at a rate identical to that of the wild-type rat DT-diaphorase. In the present study, we prepared both the wild-type human DT-diaphorase- and the mutant Q104Y-expressing MDA-MB-231 breast cancer cell lines using the cDNA transfection method. The MDA-MB-231 cell line is homozygous for a P187S mutation in the DT-diaphorase gene and has no detectable DT-diaphorase activity. Stable clones for the wild-type transfected cells had the DT-diaphorase activity ranged from 0.1 to 3.8 micromol of DCIP reduced/min/mg of protein and the clones for Q104Y transfected cells had the activity ranged from 0.06 to 1.58 micromol of DCIP reduced/min/mg of protein. Furthermore, in contrast to the cells transfected with only expression vector that were not sensitive to CB 1954 treatment, the wild-type and Q104Y-expressing cells were capable of the reductive activation of CB 1954, resulting in cell eradication. Our data showed that cell killing by CB 1954 followed a dose and incubation-time dependent manner. It was also found that the cell survival upon the treatment of CB 1954 was related to the expressed DT-diaphorase activity in these cells. In the presence of 75 microM CB 1954, a 50% cell killing was achieved in cells containing Q104Y and the wild-type DT-diaphorase with the activity at approximately 0.67 and 3.8 micromol of DCIP reduced/min/mg of protein, respectively. These results agree well with those of the in vitro enzyme assays that show that Q104Y is significantly more active than the wild-type DT-diaphorase in the activation of CB 1954. Finally, the in vivo activation of CB 1954 was demonstrated with a nude mouse model using Q104Y-transfected MDA-MB-231 cells. These studies reveal that DT-diaphorase can activate CB 1954, and human Q104Y mutant enzyme is more active than the wild-type enzyme in the intracellular reductive activation of CB 1954.
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PMID:Demonstration of the activation of prodrug CB 1954 using human DT-diaphorase mutant Q104Y-transfected MDA-MB-231 cells and mouse xenograft model. 1136 Oct 19

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 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) are members of a family of enzymes that catalyze the interconversion of weakly active sexual hormones (ketosteroids) and potent hormones (17beta-hydroxysteroids). Among the known isoforms of 17beta-HSD, the type 1 catalyzes the NAD(P)H-mediated reduction of estrone (E(1)) to estradiol (E(2)), a predominant mitogen for the breast cancer cells. Therefore, the inhibition of this particular enzyme is a logical approach to reduce the concentration of estradiol in breast tumors. To develop inhibitors of type 1 17beta-HSD activity, we hypothesized that molecules containing both hydrophobic and hydrophilic components should be interesting candidates for interacting with both the steroid binding domain and some amino acid residues of the cofactor binding domain of the enzyme. Firstly, a conveniently protected 16beta-(3-aminopropyl)-E(2) derivative was synthesized from commercially available E(1). Then, a representative of all class of NHBoc-protected amino acids (basic, acid, aromatic, aliphatic, hydroxylated) were coupled using standard procedures to the amino group of the precursor. Finally, cleavage of all protecting groups was performed in a single step to generate a series of 16beta-propylaminoacyl derivatives of E(2). The enzymatic screening revealed that none of the novel compounds can inhibit the reductive activity of type 1 17beta-HSD. On the other hand, all of these E(2) derivatives did not show any significant binding affinity on four steroid receptors including the estrogen receptor. Additional efforts aimed at improving the inhibitory potency of these steroidal derivatives on type 1 17beta-HSD without providing estrogenic activities is under investigation using a combinatorial chemistry approach.
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PMID:Chemical synthesis of 16beta-propylaminoacyl derivatives of estradiol and their inhibitory potency on type 1 17beta-hydroxysteroid dehydrogenase and binding affinity on steroid receptors. 1157 22

Detoxification of ethanol can contribute to oxidative cellular and DNA damage and, thereby, to carcinogenesis. The potential relevance of this to breast carcinogenesis is suggested by evidence that alcohol consumption is a risk factor for breast cancer. It is, however, not known whether ethanol can be metabolized in breast parenchyma. The goal of this study was to determine whether class I and/or IV alcohol dehydrogenase (ADH), medium chain ADHs that can catalyze oxidation of ethanol, are expressed in human breast parenchyma. Normal and neoplastic human breast tissue specimens were examined for class I and IV ADH mRNA by reverse transcription-PCR, for protein by immunocytochemistry and Western analysis, and for their potential to catalyze NAD(+)-dependent oxidation of ethanol. Together, the findings provide evidence that: (a) class I ADH is the medium-chain ADH that is expressed in human breast parenchyma, specifically in the mammary epithelium; (b) human breast parenchyma can support ADH-mediated oxidation of ethanol; and (c) the expression of class I ADH is dramatically reduced or abrogated in invasive breast cancers. Expression of class I ADH in normal human breast parenchyma was confirmed by probing a multiple human tissue polyA(+)RNA. The unexpected finding of virtual abrogation of expression of class I ADH in invasive breast cancer suggests that the enzyme has some "tumor suppressor" function in the mammary epithelium. The one property of class I ADH fitting this designation is its potential to catalyze the oxidation of the micronutrient/prohormone retinol to retinal, the first step in the biosynthesis of retinoic acid, the principal known mediator of the actions of retinoids important for maintaining epithelia in a differentiated state.
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PMID:Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis. 1281 Jun 34

Nonmalignant (n = 36) and malignant (n = 20) tissue samples were obtained from breast cancer and breast reduction surgeries. These tissues were characterized using multiple excitation wavelength fluorescence spectroscopy and diffuse reflectance spectroscopy in the ultraviolet-visible wavelength range, immediately after excision. Spectra were then analyzed using principal component analysis (PCA) as a data reduction technique. PCA was performed on each fluorescence spectrum, as well as on the diffuse reflectance spectrum individually, to establish a set of principal components for each spectrum. A Wilcoxon rank-sum test was used to determine which principal components show statistically significant differences between malignant and nonmalignant tissues. Finally, a support vector machine (SVM) algorithm was utilized to classify the samples based on the diagnostically useful principal components. Cross-validation of this nonparametric algorithm was carried out to determine its classification accuracy in an unbiased manner. Multiexcitation fluorescence spectroscopy was successful in discriminating malignant and nonmalignant tissues, with a sensitivity and specificity of 70% and 92%, respectively. The sensitivity (30%) and specificity (78%) of diffuse reflectance spectroscopy alone was significantly lower. Combining fluorescence and diffuse reflectance spectra did not improve the classification accuracy of an algorithm based on fluorescence spectra alone. The fluorescence excitation-emission wavelengths identified as being diagnostic from the PCA-SVM algorithm suggest that the important fluorophores for breast cancer diagnosis are most likely tryptophan, NAD(P)H and flavoproteins.
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PMID:Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003). 1461 93

The short-chain oxidoreductase (SCOR) family of enzymes includes over 2000 members identified in sequenced genomes. Of these enzymes, approximately 200 have been characterized functionally, and the three-dimensional crystal structures of approximately 40 have been reported. Since some SCOR enzymes are involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30-40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure-function features including NAD/NADP cofactor preference. For example, the correlation of aspartate or arginine residues with NAD or NADP binding, respectively, predicts the cofactor preference of more than 70% of the SCOR proteins with unknown function. The analysis of conserved residues surrounding the cofactor has revealed the presence of previously undetected CH em leader O hydrogen bonds in the majority of the SCOR crystal structures, predicts the presence of similar hydrogen bonds in 90% of the SCOR proteins of unknown function, and suggests that these hydrogen bonds may play a critical role in the catalytic functions of these enzymes.
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PMID:Rational proteomics I. Fingerprint identification and cofactor specificity in the short-chain oxidoreductase (SCOR) enzyme family. 1463 34

Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.
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PMID:Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. 1464 Oct 66

Despite intensive study, the relationship between oral contraception (OC) and breast cancer remains unclear. OCs contain a potent synthetic estrogen (ethinyl estradiol) but lower endogenous estradiol levels, and ethinyl estradiol is a weak progenitor of semiquinones, catechol estrogens capable of damaging DNA. NAD(P)H:quinone oxoreductase (NQO1) stabilizes semiquinones, thus potentially preventing genetic damage from catechol estrogens, and the NQO1 C609T polymorphism seems functionally relevant. Using data from the Shanghai Breast Cancer Study, a population-based case-control study, we investigated the relationships between OC use (20% ever using), breast cancer, and NQO1 (C/C 31% and C/T + T/T 69%) among 1,039 cases and 1,121 controls. Breast cancer was not significantly associated with NQO1 genotype. There was a significant protective association between OC after age 30 years and premenopausal breast cancer [odds ratio (OR) 0.51, 95% confidence interval (95% CI) 0.29-0.89] primarily with the NQO1 T allele (C/C OR 0.76, 95% CI 0.31-1.82; C/T + T/T OR 0.38, 95% CI 0.18-0.80; P for interaction = 0.19). The association between premenopausal breast cancer and OCs significantly differed with NQO1 genotype when using OCs for >18 months (C/C OR 2.34, 95% CI 0.92-5.99; C/T + T/T OR 0.69, 95% CI 0.38-1.25; P for interaction = 0.02). Among women with the C/C genotype, postmenopausal breast cancer was significantly associated with ever-using OCs (C/C OR 2.01, 95% CI 1.08-3.74; C/T + T/T OR 0.72, 95% CI 0.49-1.05; P for interaction < 0.01). This crossover was stronger with OC use prior to age 30 years (C/C OR 3.00, 95% CI 1.43-6.25; C/T or T/T OR 0.49, 95% CI 0.29-0.81; P for interaction < 0.01). Our results require confirmation but suggest that the OC and breast cancer association depends on the ability to invoke protection from catechol estrogens.
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PMID:Oral contraceptive use and breast cancer risk: modification by NAD(P)H:quinone oxoreductase (NQO1) genetic polymorphisms. 1529 51


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