Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four human colon cancer cell lines (SW620, LS 180, DLD-I, and HCT-15) and sub-lines isolated in vitro by selection with Adriamycin were studied for reversal of intrinsic and acquired Adriamycin resistance, using buthionine sulfoximine (BSO) to deplete cellular glutathione alone and in combination with the P-glycoprotein antagonist verapamil. GSH levels varied among the parental cell lines but did not increase with resistance. In the parental SW620, DLD-I and HCT-15 and their drug-resistant derivatives, there was no relation between the effect of the glutathione-depleting agent BSO, the mRNA expression of both selenium-dependent glutathione peroxidase (GPx) and glutathione S-transferase pi (GST pi), bulk glutathione S-transferase (GST) activity, and the degree of resistance. However, in LS 180 and its derivative sub-lines, which do not principally rely on P-glycoprotein (Pgp) for Adriamycin resistance, treatment with BSO demonstrated a relatively diminished GSH depletion and enhanced recovery. In comparison with the other acquired cell lines, BSO specifically reversed acquired resistance in the LS 180 Adriamycin-resistant subline (LS 180 Ad150) after short-term drug exposure. Furthermore, the LS 180 Ad150 cells demonstrated an increase in both GPx and GST pi mRNA expression. These observations suggest that glutathione-mediated detoxification of Adriamycin may play a role in the resistance of this sub-line. Verapamil enhanced Adriamycin cytotoxicity 1.2- to 12-fold in the intrinsically resistant cells and as much as 15-fold in cell lines with acquired resistance. Combination of BSO with verapamil resulted in additive, but not synergistic, reversal of resistance. The results underscore the complex nature of Adriamycin resistance, and suggest a role for drug-resistance-modulating agents in the treatment of colon carcinoma.
Int J Cancer 1991 Nov 11
PMID:Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. 168 79

The relationship of the rate of extraction of circulating glutathione (GSH) to the level of activity of gamma-glutamyltransferase (GGT) of hepatocytes of nodular and of cancer-bearing livers was studied in rats perfused in situ via the portal vein. Fischer adult male rats with many nodules (10 rats) or few (nine rats) liver nodules and four rats with hepatomas were compared as to their ability to remove GSH (10 microM) from the perfusate. The rate of extraction of infused GSH was directly proportional to the numbers of GGT(+)-hepatocytes in the liver tissue, inhibitable completely by adding the GGT inhibitor serine borate at 6-8 mM in the perfusate, and significantly enhanced in all rats by adding the gamma-glutamyl acceptor glycyl-glycine to the perfusate. These results suggest that nodules and cancers are able to remove GSH much more efficiently from the circulation than the surrounding liver tissue and that their enhanced GSH utilization is directly dependent on their GGT activity, which is present at much higher levels than in the surrounding tissues. The increases in GGT activity in nodule hepatocytes and enhanced ability to utilize GSH could be critical factors in the response to resistance selection of chemical hepatocarcinogenesis.
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PMID:Utilization of circulating glutathione by nodular and cancerous intact rat liver. 168 39

The cyanomorpholino derivative of doxorubicin (MRA-CN) is a DNA intercalator and alkylator that is a highly potent cytotoxin, non-cross-resistant in multidrug-resistant cells, and noncardiotoxic in comparison with doxorubicin. To further examine mechanisms of action and resistance to MRA-CN, a cell line resistant to MRA-CN, ES-2R, was established by growing a human ovarian carcinoma cell line, ES-2, in increasing concentrations of the drug. The resistant subline was 4-fold resistant to MRA-CN and cross-resistant to other DNA cross-linking agents, cisplatin (7-fold) and carmustine (3-fold), as well as to the DNA strand-breaking agents etoposide (6-fold), doxorubicin (2-fold), bleomycin (5-fold), and ionizing radiation (2-fold). In contrast, ES-2R cells were not cross-resistant to vinblastine. Several months of additional growth of ES-2R cells in MRA-CN did not yield higher, stable levels of drug resistance. A low level of P-glycoprotein was detectable in the ES-2R cells. However, the extent of intracellular accumulation of [3H]MRA-CN by this resistant cell line was identical to that of the sensitive line. The number of DNA cross-links formed by cisplatin in ES-2R was only 50% of that of the ES-2 cells and was associated with a 50% increase in the rate of repair of these cross-links in the resistant cells. Ionizing radiation induced similar amounts of single- and double-strand breaks in the ES-2 line as well as in the ES-2R cells. There was no apparent difference between the two cell lines in the rate and extent of repair of these DNA breaks. Thus, enhanced DNA repair cannot explain the phenomenon of cross-resistance to radiation. Comparisons of glutathione (GSH) content and the enzymes involved in GSH homeostasis showed significant differences. Resistant cells contained 1.5-fold more GSH, a 2.2-fold increase in gamma-glutamyltranspeptidase activity, and a 2.4-fold increase in GSH reductase compared with ES-2 cells (all P less than 0.05). Total glutathione-S-transferase (GST) activity was 2.6-fold higher (P less than 0.01) in the ES-2R line. The pi-class GST subunit by Western blotting and GST activity toward ethacrynic acid were increased 2-fold in the resistant cells. Depletion of GSH levels in ES-2R cells by buthionine sulfoximine restored the sensitivity of ES-2R to MRA-CN. These findings implicate a role for GSH metabolism in the resistance phenotype of ES-2R cells. We have previously reported that these cells have an increased generation time and decreased topoisomerase II content. Thus, the ES-2R cell line exhibits a complex phenotype of broad cross-resistance, which is likely to involve multiple mechanisms, and includes enhanced DNA repair and increased GSH content and GST activity.
Cancer Res 1991 Oct 01
PMID:Multifactorial mechanisms associated with broad cross-resistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin. 171 40

Deviations of the enzyme activity, immunoreactivity and messenger ribonucleic acid (mRNA) levels of glutathione peroxidase (GSH-PO) in 3'-methyl-4-dimethylaminoazobenzene- induced hepatocellular carcinoma of the rat were investigated. Enzyme activities of GSH-PO were significantly lower in hepatocellular carcinomas than those in the normal control rat liver. Immunohistochemically, GSH-PO was strongly localized in normal hepatocytes, but was only faintly stained in hepatocellular carcinoma cells. Heterogeneous staining patterns of GSH-PO were observed among individual cancer cells. In Northern blot analysis, GSH-PO mRNA in the cancer tissue was decreased to two thirds of the level in normal hepatocytes. It was suggested that suppressed expression of GSH-PO in carcinogen-induced hepatocellular carcinomas occurred at the level of mRNA transcription.
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PMID:Suppression of messenger ribonucleic acid for glutathione peroxidase in chemically induced rat hepatocellular carcinoma and its biological significance. 171 59

Selenium has been reported to affect glutathione (GSH) concentrations in short-term animal-feeding experiments. Given the central role that this tripeptide plays in maintaining cellular homeostasis, it was hypothesized that perturbations in glutathione metabolism induced by selenium might account for its cancer chemopreventive activity. In the present study, four experiments were conducted in which the effect of acute, short-, or long-term exposure to selenium was assessed. Selenium was provided as either sodium selenite or D,L-selenomethionine. Selenite was observed to induce a biphasic response in total liver GSH. Injected selenium caused an acute reduction in GSH, whereas short-term feeding (up to 8 wk) increased both total GSH and oxidized glutathione (GSSH), an effect that gradually diminished in magnitude with prolonged feeding. Our data suggest that such changes are unlikely to account for the chemopreventive activity of selenium for the following reasons: Perturbations in glutathione metabolism occurred only at doses of selenite that approached toxicity. These doses are higher than what would be required for producing cancer chemoprevention. The transient nature of these changes also contrasts with the need for a continuous supplementation of selenite in suppression of tumorigenesis. Furthermore, selenomethionine was found to have little activity in altering glutathione metabolism, even though it compares favorably with selenite as a cancer chemopreventive agent. Nonetheless, these findings do not discount the possibility that sulfhydryl compounds, such as glutathione, might be used to modify the toxicity and/or enhance the cancer prophylactic activity of selenium compounds.
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PMID:Temporal changes in tissue glutathione in response to chemical form, dose, and duration of selenium treatment. Relevance to cancer chemoprevention by selenium. 172 87

The effect of vitamin K3 (2-methyl-1,4-naphthoquinone) on Adriamycin (ADR) induced growth inhibition of drug sensitive and multidrug resistant P388 leukemia cells was evaluated. Exposure to ADR concentrations of 100-5000 ng simultaneously with 1 microM vitamin K3 elicited an enhanced inhibition of tumor cell survival. The effect of treatment with ADR alone, or in combination with vitamin K3 on DNA and RNA biosynthesis in the sensitive and resistant tumor cells, was also assessed. DNA and RNA biosynthesis inhibition was increased in P388/S (the parental cell line) and P388/ADR cells (the ADR resistant cell line which exhibits the multidrug resistant (MDR) phenotype) exposed to ADR after pretreatment for 3 h with vitamin K3. Concurrent administration in vivo of vitamin K3 and ADR illustrated a therapeutically significant increase (P less than 0.05) in the life span of sensitive and resistant tumor cell bearing animals. Vitamin K3 caused a depletion of the intracellular glutathione (GSH) levels in P388/S and P388/ADR leukemia cells but at concentrations greater than those that enhanced ADR cytotoxicity. Pretreatment of the tumor cells with 1 microM vitamin K3 induced a 35-50% (P less than 0.001) elevation in the intracellular ADR accumulation in MDR P388 leukemia cells, while such an effect was absent in P388/S tumor cells. DNA binding studies performed utilizing calf thymus DNA, indicated that vitamin K3 enhanced the intercalation potential of ADR and also altered the equilibrium between the free and bound form of ADR in a cell free system. These factors and their possible effects on the potentiation of ADR cytotoxicity and the therapeutic significance of utilizing vitamin K3 as an adjuvant in the chemotherapy of MDR tumors is discussed.
Cancer Lett 1992 Jan 10
PMID:Circumvention of adriamycin resistance: effect of 2-methyl-1,4-naphthoquinone (vitamin K3) on drug cytotoxicity in sensitive and MDR P388 leukemia cells. 173 Jan 38

Based on findings that the cytotoxic effects of tumor necrosis factor (TNF) are closely related to levels of intracellular oxygen radicals, and on the results of TNF gene transfection studies, the hypothesis was made that endogenous TNF (enTNF) acts as a protective factor against exogenous TNF by inducing inhibitors or scavengers of oxygen radicals. In order to test this hypothesis, we investigated the intracellular levels of manganous superoxide dismutase (MnSOD) and glutathione (GSH) in L-M(pNTnF) cells carrying a TNF gene induced by dexamethasone (DM). When L-M(pNTnF) cells were treated with DM they expressed enTNF, and acquired resistance to exogenous TNF. There was no change in the GSH concentration after enTNF induction, but a 1.9- to 3.9-fold increase in MnSOD levels was noted. Our findings suggest that enTNF exerts its protective function against the cytocidal effect of exogenous TNF by inducing MnSOD production.
Int J Cancer 1992 Feb 01
PMID:Induction of synthesis of manganous superoxide dismutase in L-M(pNTnF) cells carrying an inducible TNF gene. 173 14

The present studies demonstrate that the ability of supplemental selenite to alter the in vitro growth of canine mammary tumor cell line 13 was dependent on the quantity and duration of selenium exposure and on the culture density. Exposure to 3.2 microM selenite did not significantly alter growth but led to an increase in intracellular glutathione (GSH). The severity of growth inhibition between 3.2 and 9.6 microM selenite was dependent on the duration of exposure and culture density. The toxicity of selenite generally increased as the culture density increased. Likewise, changes in intracellular GSH were dependent on the quantity and duration of selenite exposure and the culture density. Depressing intracellular GSH by increasing the culture density or by incubating with buthionine sulfoximine; a specific inhibitor of gamma-glutamyl cysteine synthetase, increased the severity of growth inhibition caused by selenite and markedly increased cellular retention of selenium. Nevertheless, marked cellular retention of selenium did not occur until growth was inhibited by more than 50%. The present studies revealed that the log of the molar ratio of GSH to selenium correlated negatively with the severity of growth inhibition (P less than 0.0001). These studies suggest that cellular toxicity of selenite is dependent on the regulation of the GSH:selenium ratio. An inability to regulate this ratio likely leads to the accumulation of toxic seleno compounds.
Cancer Res 1992 Mar 01
PMID:Influence of intracellular glutathione on selenite-mediated growth inhibition of canine mammary tumor cells. 173 67

Whole-body autoradiography of 3H-labeled aflatoxin B1 (AFB1) in adult C57BL mice pretreated with the glutathione (GSH)-depleting agent phorone showed accumulation of tissue-bound radioactivity in the nasal olfactory and respiratory mucosa, the mucosa of the nasopharyngeal duct, and the tracheal and esophageal mucosa, which was not seen in unpretreated adult mice. The altered distribution pictures induced by the phorone are probably related to decreased tissue levels of GSH. The AFB1 is likely to be bioactivated locally in the extrahepatic tissues; in nonpretreated mice the reactive AFB1 metabolite formed is probably scavenged by GSH via the action of glutathione-S-transferase, whereas in the mice with depleted GSH levels a binding to tissue macromolecules will instead take place. The mechanism indicated above is supported by results of in vitro experiments in which the nasal olfactory mucosa and the esophageal mucosa were shown to have a capacity to form tissue-bound 3H-AFB1 metabolites. This formation was decreased when the incubations were performed in the presence of GSH. In addition, the treatments of mice with phorone were shown to induce a strong GSH depletion in the nasal olfactory mucosa and the esophageal mucosa. In autoradiographic studies performed with 1- and 5-day-old infant mice a marked localization of bound 3H-AFB1 metabolites was found in the nasal olfactory mucosa, and in the 5-day-old infant there was also a labeling of the mucosa of the nasopharyngeal duct, the pharyngeal and esophageal mucosa, and the tracheal mucosa. Experiments in vitro with the nasal olfactory mucosa of 5-day-old infants demonstrated a marked binding of 3H-AFB1 metabolites in this tissue. Incubations together with GSH decreased this binding, although the inhibition was less marked than in the adult animal. The in vivo accumulation of bound AFB1 metabolites in the extrahepatic tissues of the infant mice may be related to low glutathione-S-transferase (GST) activity in the tissues of the young animals. In addition, some extrahepatic tissues may have a considerable capacity to bioactivate the AFB1 at early age. Autoradiography of 3H-AFB1 in pregnant mice showed a labeling of the fetal nasal olfactory mucosa at day 18 but not at day 14 of gestation. This indicates that AFB1-bioactivating enzymes develop in the fetal nasal olfactory mucosa in late gestation.
Cancer Res 1992 Mar 01
PMID:Binding of aflatoxin B1 metabolites in extrahepatic tissues in fetal and infant mice and in adult mice with depleted glutathione levels. 173 89

Piperine is known to modify the biotransformation of drugs. The effect of piperine on the metabolic activation and distribution of [3H]-aflatoxin B1 (AFB1) in rats has been described. Piperine markedly inhibited liver microsome-catalysed [3H]AFB1 binding to calf thymus DNA in vitro, in a dose dependent manner. Rats pretreated with piperine accumulated considerable [3H]AFB1 radioactivity in plasma and in the tissues examined as compared to the controls. However, piperine had no influence on hepatic [3H]AFB1-DNA binding in vivo, which could possibly be due to the null effect of piperine on liver cytosolic glutathione (GSH) 5-transferase activity. Piperine-treated rat liver microsomes demonstrated a tendency to enhance [3H]AFB1 binding to calf thymus DNA in vivo. The effect of piperine on AFB1 metabolism thus closely resembles the mode of action of SKF 525-A on biotransformation of foreign compounds.
Cancer Lett 1992 Jan 31
PMID:Piperine, a plant alkaloid of the piper species, enhances the bioavailability of aflatoxin B1 in rat tissues. 173 43


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