Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue concentrations of glutathione (GSH) and the activity of glutathione S-transferases (GST) are relevant to the inactivation of a variety of xenobiotics including carcinogens and anti-neoplastic drugs. In this study, GSH concentrations and GST activity were determined in 25 adenomatous polyps removed at colonoscopy, and in cancer and uninvolved 'normal' mucosa from 58 operative specimens containing colon cancer. We also examined the relationship between GSH concentrations, GST activity and rates of cell proliferation as assessed by flow cytometry. Concentrations of GSH were significantly higher in adenomas (P = 0.001) and cancer (P = 0.001) than in uninvolved mucosa while GST activity was significantly higher in cancer (P = 0.007). There was a positive relationship between GSH concentrations and GST activity in adenomas (P = 0.001) but not in uninvolved mucosa (P = 0.06) or cancer (P = 0.4). Concentrations of GSH and GST activity were independent of results from flow cytometry. The higher concentrations of GSH in colonic neoplasms and the raised activity of GST in cancer may contribute to their resistance to anti-neoplastic drugs.
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PMID:Glutathione concentrations and glutathione S-transferase activity in human colonic neoplasms. 815 68

Erythrocyte activity of glutathione peroxidase (GSH-Px) was measured in 26 patients with colon cancer and in 26 sex, age, height and weight matched controls. The patient group had a lower mean GSH-Px activity than the control group (p < 0.001). No correlation was found between glutathione peroxidase activity and sex, age, height, or weight, or between glutathione peroxidase activity and duration of the disease. The inverse correlation between the activity of this enzyme and the extent of the disease may be caused by a decreased absorption of selenium from the diseased colon. The significance of decreased GSH-Px in patients with this disease is unknown, but the possibility exists that this may further increase their risk of developing colonic cancer.
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PMID:Erythrocyte glutathione peroxidase in patients with colon cancer. 835 Sep 54

To examine the influence of hypercholesteremia on 1,2-dimethylhydrazine (DMH)-induced rat colon cancer, Sprague-Dawley rats received dietary cholesterol (CH, 0-2%) and cholic acid (CA, 0.25%) with or without DMH (20 mg/kg, s.c. injection) for 18 weeks. The rats receiving dietary cholesterol and cholic acid all significantly increased total serum cholesterol and lipids but only a high cholesterol diet (2% CH plus 0.25% CA) decreased the activity of glutathione peroxidase (GSH-Px) and increased the formation of peroxides in the colon (P < 0.01). The rats that received the combination of DMH and high cholesterol diet enhanced these effects. At the end of the experiment, the diet group administered DMH and high cholesterol (2% CH plus 0.25% CA) developed colon adenoma at 50% of incidence in pathological examination, but no colon adenoma formed in the rats treated with high cholesterol alone. It is supposed that a non-carcinogenic agent like cholesterol may potentiate the carcinogenicity of DMH in rats via an increase of lipid peroxidation and decrease in the activity of peroxidase in the target organ.
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PMID:Promotion of colon carcinogenesis through increasing lipid peroxidation induced in rats by a high cholesterol diet. 862 Apr 57

The formation of the glutathione S-conjugate of monochlorobimane (GSH-bimane) in human colon adenocarcinoma cells was identified by HPLC-fluorimetry and its transport from the cells was found to be temperature-sensitive, saturable and ATP-dependent. The apparent K(m) and Vmax values were 2.4 +/- 0.5 nmol GSH-bimane/10(6) cells and 0.5 +/- 0.1 nmol GSH-bimane/min per 10(6) cells, respectively. This active transport of GSH-bimane was inhibited by low micromolar concentrations of classical uncouplers of oxidative phosphorylation, namely carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), carbonylcyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP). The efflux of GSH-bimane was competitively inhibited by chlorambucil (CMB) and 1-chloro-2,4-dinitrobenzene (CDNB), two other substrates of GST. This study demonstrates the presence and kinetic measurements of the glutathione S-conjugate export (GS-X) pump in human colon cancer cells, an export pump whose function has been implicated in the phenomenon of multidrug resistance.
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PMID:Active transport of glutathione S-conjugate in human colon adenocarcinoma cells. 895 Feb 21

It has been demonstrated that nitric oxide (NO) can promote apoptosis in human cancer cells. To test the protective effects of antioxidants (N-acetyl-L-cysteine (LNAC) and free-radical spin traps (5,5-dimethyl-1-pyrroline N-oxide and 2,2,6,6,-tetramethyl-1-piperidinyloxy) against NO-induced apoptosis, a human colon cancer cell line (COLO 205) was treated with NO, and its survival rate was evaluated both with and without antioxidant therapy. LNAC arrested the development of progression of apoptosis in COLO 205 cells in a dose-dependent manner, promoted long-term survival, and prevented the internucleosomal DNA cleavage induced by NO. The intracellular level of glutathione (GSH) was found to be elevated in cells after exposure to LNAC. The bax protein levels were elevated by NO treatment, and this effect was blocked by LNAC. On the other hand, the bcl-2 oncoprotein level in the LNAC-pretreated cells was significantly elevated in a time-dependent manner compared to cells that received NO pretreatment. In summary, our results suggest that the protective effect of LNAC may be linked to its inducement of increases in cellular GSH and bcl-2 protein levels and to its suppression of cellular bax protein in treated cells.
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PMID:Suppression of nitric oxide-induced apoptosis by N-acetyl-L-cysteine through modulation of glutathione, bcl-2, and bax protein levels. 921 Sep 57

Maintenance of cellular homeostasis is a critical survival trait in tumors when exposed to anticancer drugs. Because conjugation and elimination of drugs and their metabolites is dependent upon sequential and coordinated pathways, acquired drug resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in the expression of one gene product. We have used a number of drug-resistant human cell lines to characterize those genes that are implicated in maintaining a resistant phenotype. Human HT29 colon cancer cells chronically exposed to ethacrynic acid (EA) [a glutathione (GSH) and glutathione S-transferase (GST) modulator] have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include: gamma-glutamyl cysteine synthetase (gamma-GCS, the rate-limiting enzyme in GSH biosynthesis); GST pi (the enzyme catalyzing the conjugation reaction); multidrug resistance associated protein (MRP) (the membrane pump responsible for effluxing the conjugate from the cell interior). In addition, other gene products not directly linked with EA metabolism were induced, including dihydrodiol dehydrogenase (an alpha-ketoreductase) (30-fold), DT-diaphorase (threefold), and a transcriptional regulator SSP 3521 (threefold). HL60 cells resistant to a GSH paralog Ter199 also show increased expression of some of these gene products. Furthermore, an adriamycin-resistant human HL60 cell line also shows overexpression of GST pi, gamma-GCS, and MRP, but in addition has approximately 20-fold more DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This enzyme is an early stress response gene that can phosphorylate and activate downstream transcription factors. Such overexpression could impact on the transcriptional control of the other detoxification gene products. Both adriamycin and a typical drug-GSH conjugate (APA-SG) are inhibitors of DNA-PK. Because cellular levels of these conjugates would presumably be a good indicator of stress, it would seem reasonable to speculate that DNA-PK may act as a receiver and transmitter of signals that are crucial to the drug-resistant phenotype. Additionally, this enzyme may prove to be a potentially important target for drug design based upon the inhibitory activity of GSH conjugates.
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PMID:Importance of glutathione and associated enzymes in drug response. 940 35

Glutathione S-transferases (GST) alpha and pi, glutathione (GSH) and aldehyde dehydrogenase (ADH) were determined in colorectal cancer tissue specimens and in the adjacent normal colon tissue. The median contents in normal and cancer tissue were 8.1 (2.3-30.3) (5-95% quantiles) and 15.1 (5.3-50.3) microg/mg protein for GST pi (P = 0.035), 0.0 (0.0-1.4) and 0.4 (0.0-3.5) microg/mg protein for GST alpha (P = 0.019), 7.3 (1.3-22.7) and 5.6 (2.3-26.0) microg/mg protein for GSH (P = 0.171) and 30.8 (13.0-42.0) and 23.2 (9.0-32.9) microg/mg protein for ADH (P = 0.0017), respectively. Thus, the mean GST alpha and pi both significantly increased in colon cancer compared to the adjacent normal tissue, which underlines their importance as possible resistance factors. A highly significant correlation was obtained between the GSH content in colon cancer and normal tissue (P = 0.0017). Thus, the constitutive GSH expression seems to be maintained during tumor development. A similar correlation was obtained for ADH (P = 0.0075), but the median ADH was lower in cancer tissue compared to the adjacent normal tissue (P = 0.0017). Contrary to GSH and ADH, GST pi did not correlate between normal and colon cancer tissue. Whereas GSH and ADH correlated in normal colon tissue (P = 0.014), no significant correlation for GSH and ADH was observed in colon cancer tissue (P = 0.109). In conclusion, significant correlations between colon cancer and normal tissue were obtained, suggesting that the expression levels of these resistance factors are maintained during carcinogenesis in most patients.
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PMID:Resistance factors in colon cancer tissue and the adjacent normal colon tissue: glutathione S-transferases alpha and pi, glutathione and aldehyde dehydrogenase. 965

Maintenance of cellular homeostasis is a critical survival trait when cells are exposed to electrophilic chemicals. Because conjugation and elimination of these toxins is dependent upon sequential and coordinated metabolic pathways, acquired resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in one gene product. Human HT29 colon cancer cells chronically exposed to EA have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include gamma-GCS (approximately 3-fold), GST-pi (approximately 3-fold), MRP (approximately 3-fold), NQO1 (approximately 3-fold), DDH (20-fold), and SSP 3521, a transcriptional regulator (approximately 3-fold). Multiple mechanisms contribute to these increases, including enhanced transcriptional rate and prolonged mRNA and protein half lives. Further indications for the involvement of transcriptional regulators is found in HL60 adriamycin-resistant cells which overexpress MRP, GST-pi and gamma-GCS and also have 15-20-fold more DNA-dependent protein kinase. It is possible that this enzyme serves as an early stress response gene which may activate downstream transcription factors. Intriguingly, the catalytic subunit of DNA-dependent protein kinase has a high avidity for [35S]azidophenacyl-GSH. High levels of GSH conjugates indicate cell stress and it would seem reasonable to speculate that DNA-dependent protein kinase may serve as a receiver and transmitter of signals which contribute to drug resistance and maintain cell viability.
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PMID:Coordinate changes in expression of protective genes in drug-resistant cells. 967 55

Thioredoxin (TRX) is a widely distributed Mr 13,000 protein with a redox-active dithiol/disulfide in the active site. The TRX system, consisting of TRX, TRX reductase, and NADPH, has an intracellular reducing capacity. Another reducing capacity, glutathione (GSH), can be associated with cis-diaminedichloroplatinum (cDDP) resistance. Therefore, we examined the involvement of TRX in cDDP resistance using two cell lines designated St/DDP and HT/DDP, which were established from the human gastric cancer cell line St-4 and the colon cancer cell line HT-29. St/DDP and HT/DDP were seven and five times as resistant to cDDP as their parental lines, and the expression of TRX in these variants was increased by 2.5- and 2-fold, respectively. The expression of TRX in the complete revertant cells of St/DDP was reduced as low as that in St-4 cells. TRX reductase activity was also increased in St/DDP and HT/DDP, suggesting that activation of the TRX system was associated with in vitro-acquired cDDP resistance. Because cDDP is the first-line drug against ovarian cancer, we examined the expression of TRX in 11 human ovarian cancer cell lines not treated with cDDP in vitro. Positive correlation between TRX expression and cDDP resistance was observed in these cell lines (r = 0.76, P = 0.007). This correlation was comparable to that between GSH content and cDDP resistance (r = 0.69, P = 0.019). These results suggest a possible involvement of TRX, as well as GSH, in cDDP resistance.
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PMID:Increased expression of thioredoxin/adult T-cell leukemia-derived factor in cisplatin-resistant human cancer cell lines. 981 87

A network composed of activation and inactivation pathways to regulate mitomycin C (MMC) action is suggested to exist in human cancer cells. COLO201 colon cancer cells were stably transfected with human NQO1 cDNA that encodes NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD), and a clonal cell line with about 57-fold elevated DTD activity was obtained. Northern analysis revealed that expression of the NADPH:cytochrome P450 reductase (P450 reductase) gene was decreased in the transfectant, COLO201/NQO1, associated with the increase of NQO1 expression. Biochemical characterization of the cells showed a significant increase of the glutathione (GSH) content concomitantly with the decrease of the P450 reductase activity. As a result of these coordinated modulations, sensitivity of COLO201/NQO1 to MMC was not increased as compared to the parent cells. Analyses of inhibition by specific inhibitors of DTD, P450 reductase and glutathione S-transferase (GST) in 5 human colon cancer cell lines including the transfectant showed that DTD and P450 reductase play significant roles in MMC activation in cells with sufficiently high DTD activity and with marginal DTD activity, respectively. In contrast, GST appeared to participate in MMC inactivation in cells with a high level of GST activity. These results indicated that DTD, P450 reductase, GSH and GST may act together compensatively or competitively, depending on their levels in cells, to determine the cellular sensitivity to MMC.
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PMID:Regulatory network of mitomycin C action in human colon cancer cells. 1039 Oct 98


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