Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

We recently reported that GS-X pump activity, as assessed by ATP-dependent transport of the glutathione-platinum complex and leukotriene C4, and intracellular glutathione (GSH) levels were remarkably enhanced in cis-diamminedichloroplatinum(II) (cisplatin)-resistant human leukemia HL-60 cells (Ishikawa, T., Wright, C. D., and Ishizuka, H. (1994) J. Biol. Chem. 269, 29085-29093). Now, using Northern hybridization and RNase protection assay, we provide evidence that the multidrug resistance-associated protein (MRP) gene, which encodes a human GS-X pump, is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells, whereas amplification of the MRP gene is not detected by Southern hybridization. Culturing HL-60/R-CP cells in cisplatin-free medium resulted in reduced MRP mRNA levels, but these levels could be induced to rise within 30 h by cisplatin and heavy metals such as arsenite, cadmium, and zinc. The increased levels of MRP mRNA were closely related with enhanced activities of ATP-dependent transport of leukotriene C4 (LTC4) in plasma membrane vesicles. The glutathione-platinum (GS-Pt) complex, but not cisplatin, inhibited ATP-dependent LTC4 transport, suggesting that the MRP/GS-X pump transports both LTC4 and the GS-Pt complex. Expression of gamma-glutamylcysteine synthetase in the cisplatin-resistant cells was also co-induced within 24 h in response to cisplatin exposure, resulting in a significant increase in cellular GSH level. The resistant cells exposed to cisplatin were cross-resistant to melphalan, chlorambucil, arsenite, and cadmium. These observations suggest that elevated expression of the MRP/GS-X pump and increased GSH biosynthesis together may be important factors in the cellular metabolism and disposition of cisplatin, alkylating agents, and heavy metals.
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PMID:Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. 866 1

We have recently shown that multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit genes are coordinately overexpressed in cisplatin-resistant human leukemia cells (T. Ishikawa et al. J. Biol. Chem., 271: 14981-14988, 1996). Using the RNase protection assay, we examined expression levels of these genes in colon tumor and nontumorous biopsy specimens from 32 cancer patients who had not been treated with chemotherapy. Increased mRNA levels (P < 0.001) of MRP and gamma-GCS genes were observed in 16 (50%) and 20 (62%) tumor samples, respectively. More importantly, all of the 16 (100%) MRP-overexpressing tumor specimens also exhibited higher levels of gamma-GCS mRNA than those in the matched nontumorous specimens. The correlation coefficient between MRP and gamma-GCS mRNA levels was r = 0.78 for all of the tumor samples studied. These results strongly suggest that MRP and gamma-GCS genes are coordinately up-regulated during colorectal carcinogenesis.
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PMID:Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers. 870 99

Expression of the multidrug-resistance protein gene MRP, which confers non-P-glycoprotein-mediated multidrug resistance, has been found in many drug-resistant variants and tumor samples. Recent studies have demonstrated that MRP functions as an ATP-dependent transporter functionally related to the previously described glutathione-conjugate (GS-X) pump. We have shown recently that the MRP and gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit mRNA levels are coordinately overexpressed in cisplatin (CP)-resistant human leukemia cells (Ishikawa et al., J Biol Chem 271: 14981-14988, 1996) and frequently co-elevated in human colorectal tumors (Kuo et al., Cancer Res 56: 3642-3644, 1996). In the present study, we showed the coexpression patterns of thirteen additional human drug-resistant cell lines representing different tumor cell origins selected with different agents, except for one doxorubicin-selected line which demonstrated minor elevation in MRP mRNA with no detectable increase in gamma-GCS mRNA, suggesting that the increase of MRP mRNA preceded the increase in gamma-GCS mRNA. Furthermore, in seventeen randomly selected untreated tumor cell lines, the overall correlation coefficient between MRP and gamma-GCS mRNA levels was 0.861. In normal mice, the correlation coefficient of mrp and gamma-gcs mRNA was 0.662 in fourteen tissues (kidney and liver were not included) analyzed. Kidney and liver expressed low levels of mrp relative to gamma-gcs; however, these two tissues expressed high levels of a functionally related mrp homologue, mrp2 (cMoat or cMrp), which may have compensated for the underexpressed mrp in maintaining the total GS-X pump activities. Altogether, these results demonstrated the frequent coexpression of these two genes in various cell settings.
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PMID:Frequent coexpression of MRP/GS-X pump and gamma-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues. 951 71

Elevation of activity and mRNA level of a cytosolic aldehyde dehydrogenase-1 (ALDH1), which oxidizes aldophosphamide, was previously observed in a cyclophosphamide-resistant murine leukemia cell line. However, changes in other enzyme(s) which may detoxify the drug or produce anti-alkylating agent(s), have not been examined. The human leukemia cell line, K562, was made 30-fold resistant against 4-hydroperoxycyclophosphamide (4HC) by exposing the cells to increasing concentrations of the drug. Resistance against cisplatin was also increased by about 3-fold. Activities of glucose-6-phosphate dehydrogenase (G6PD) and ALDH1 were elevated more than 7-fold in the resistant cells. The mRNA level of the two enzymes was also proportionally elevated. The concentration of reduced glutathione (GSH) was higher in the resistant cells (i.e., 21.1 versus 4.68 nmole per 10(6) cells), while activities of gamma-glutamylcysteine synthetase and glutathione synthetase, and the expressions of other human ALDH genes were not increased in the resistant cells. These findings suggest that the acquired resistance against 4HC is a consequence of transcriptional activation of two genes, i.e., one encoding the G6PD, a major enzyme regenerating anti-alkylating GSH, and the other encoding ALDH1, which has a high activity for oxidation of aldophosphamide derived from 4HC.
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PMID:Enhanced expressions of glucose-6-phosphate dehydrogenase and cytosolic aldehyde dehydrogenase and elevation of reduced glutathione level in cyclophosphamide-resistant human leukemia cells. 971

Homeostatic mechanisms for the maintenance of glutathione (GSH) are fundamental in the provision of a cellular defense against electrophilic/oxidant challenges. Cyclopentenone prostaglandins (CP-PGs) are powerful antiproliferative endogenous substances that may act as electrophilic regulating compounds, by virtue of the presence of an alpha,beta-unsaturated carbonyl group in the cyclopentane ring. Nevertheless, differential resistance to CP-PG cytotoxic/cytostatic effect has been reported in different cell types. It is reported that the activity/expression of gamma-glutamylcysteine synthetase (gamma-GCS, the rate-limiting enzyme in GSH biosynthesis) can be inducibly activated by electrophiles, including CP-PGs. The response of the human cancer strains HEp-2 (larynx carcinoma) and HL-60 (promyelocytic leukemia) cells to treatment with the CP-PG PGA1 in culture was investigated by evaluating the time-course of GSH synthesis and activity of enzymes of GSH metabolism, other than gamma-GCS, after PGA1 addition. HEp-2 cells, being more resistant to PGA1 cytotoxic and cytostatic effects, have basal GSH levels that were 2.4-fold higher than that of HL-60 cells. The activities of GSH S-transferase (GST), glutathione reductase (GSRd) and glutathione peroxidase (GSPx) are constitutively higher in HL-60 cells than in HEp-2 cells (respectively, 17.0-, 28.5- and 12.3-fold). When challenged with PGA1, both cell types exhibited a dose-dependent rise in GSH content that was maximal 18 h after PGA1 addition and was preceded by a rise in GST and GSRd activities in both cell types (at 12 h). GSPx activity increased only in HEp-2 (PGA1 evoked a 93.4%-inhibition in HL-60 cells). Moreover only HEp-2 cells exhibited early capacity to enhance GSH content (1-2 h just after PGA1 addition). These results and earlier data showing that leukemia cells are sensitive to CP-PG treatment suggest that deficiencies in GSH metabolism may be strategically in therapeutic approaches to the treatment of human leukemias.
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PMID:Effects of the antiproliferative cyclopentenone prostaglandin A1 on glutathione metabolism in human cancer cells in culture. 976 23

Nitric oxide (NO) has been shown to be cytotoxic for normal and transformed cell lines. One of the intracellular targets for NO action is glutathione (GSH). GSH determinates cellular redox potential and modulates several biological events. During oxidative and nitrosative stress, glutathione system imbalance is associated with the upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, which is mediated by nuclear factor kappaB (NF-kappaB). Our previous studies demonstrated a cytotoxic effect of NO and taxol on human lymphoblastic leukemia cells triggered by inhibition of NF-kappaB activity. In this study, we have demonstrated the involvement of GSH in taxol- and NO-induced cytotoxic effects on human CEM leukemia cells. NO- and taxol-induced a depletion of GSH levels in CEM cells, which was potentialized by l-buthionine-S,R-sulfoximine (BSO), an inhibitor of gamma-GCS. BSO induced an increase in nuclear translocation of NF-kappaB. However, when cells were treated with NO or taxol in association with BSO, these compounds inhibited the constitutive activity of NF-kappaB. These results suggest that oxidative and nitrosative damage in lymphoblastic leukemia cells shall be mediated by NO- and taxol-induced GSH depletion as a consequence of preventing GSH synthesis.
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PMID:Involvement of NF-kappaB and glutathione in cytotoxic effects of nitric oxide and taxol on human leukemia cells. 1607 90

Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti-leukemia reagents. Hemin treatment of human BCR/ABL-positive KCL22 leukemia cells increased IC(50) values of imatinib, that is, the drug resistance, in a dose-dependent manner without any change in the BCR/ABL kinase activity. Imatinib-induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of gamma-glutamylcysteine synthetase (gamma-GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of gamma-GCS and heme oxygenase-1 (HO-1), two MARE-containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib-treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin-mediated protective effect. Similar to hemin, treatment of cells with delta-aminolevulinic acid (delta-ALA), the obligatory heme precursor, also increased IC(50) values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL-negative leukemia U937 and THP-1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti-leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity.
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PMID:Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. 1817 53

The biological function as well as gene expression of the MRP/GS-X pump is closely linked with cellular GSH metabolism. This article describes two important aspects, i.e., 1) a role of the MRP/GS-X pump in the modulation of cell cycle arrest induced by anticancer prostaglandins; 2) coordinated up-regulation of gamma-glutamylcysteine synthetase gamma-GCS) and MRP1 genes. The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Delta(7)-Prostaglandin A(1) (Delta(7)-PGA(1)) methyl ester, a synthetic anticancer PG, increased the mRNA level of the cyclin-dependent kinase inhibitor p21(Sdi1/CIP1/WAF1) in human leukemia HL-60 cells. The induction of p21(Sdi1/CIP1/WAF1) was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta(7)-PGA(1) methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anticancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump activity toward the glutathione S-conjugate of Delta(7)-PGA(1) methyl ester. GIF-0019, a potent inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta(7)-PGA(1) methyl ester, resulting in G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anticancer PG. The expression of MRP1 and gamma-GCS genes can be coordinately up-regulated by cisplatin, 1-[5-(4-amino-2-methyl)pyrimidyl]methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), and heavy metals in human cancer cells. For the up-regulation of these genes, both transcriptional and posttranscriptional regulations are considered to be involved.
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PMID:A new aspect on glutathione-associated biological function of MRP/GS-X pump and its gene expression. 1900 85

Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibits cyclooxygenases, is able to overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 10 microM increased the cytotoxicity of doxorubicin and vincristine in K562/ADR cells. Intracellular glutathione content was elevated in K562/ADR cells. Indomethacin treatment decreased glutathione content and glutathione-conjugates in K562/ADR cells. Increased expression of gamma-glutamylcysteine synthetase (gamma-GCS) was observed in K562/ADR cells, but this expression was decreased by indomethacin treatment. The activity of the gamma-GCS promoter from K562/ADR cells decreased after indomethacin treatment in MDA231 cells. These data strongly suggest that the cyclooxygenase inhibitor indomethacin increases the cytotoxicity of doxorubicin by decreasing the intracellular contents of glutathione and its conjugates with decreasing expression of gamma-GCS by inhibiting gamma-GCS promoter activity.
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PMID:Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells. 1915 36


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