Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance of cancer cells is often accompanied by the (over)expression of integral plasma membrane P-glycoprotein, an ATP-dependent transport pump for diverse unrelated compounds. The glutathione detoxification system represents another mechanism that may be involved in multidrug resistance. In the multidrug-resistant L1210/VCR cell line obtained by long-term adaptation of parental L1210 cells to vincristine, an increased expression of P-glycoprotein has previously been established. In this paper, we investigated if the glutathione detoxification system is also involved in the multidrug resistance of these cells. L1210/VCR cells with resistance induced by adaptation to vincristine were also found to be cross-resistant to vinblastine, actinomycin D, mitomycin C, doxorubicin and cyclophosphamide. The resistance of the above cells to vincristine and doxorubicin was accompanied by a depression of drug accumulation (which has not yet been established for other drug). L1210/VCR cells are able to survive better than sensitive cells under conditions when glutathione was depleted by L-buthionine sulfoximine. Nevertheless, L-buthionine sulfoximine did not influence the resistance of L1210/VCR cells to vincristine. Moreover, the presence of sublethal concentrations of cytostatics neither changed the IC50 value of resistant cells to L-buthionine sulfoximine nor the cytoplasmic activity of glutathione S-transferase, the crucial enzyme of glutathione detoxification system. All the above findings indicate that the glutathione detoxification system is not involved in the mechanisms that ensure the multidrug resistance phenotype of L1210/VCR cells.
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PMID:Glutathione S-transferase does not play a role in multidrug resistance of L1210/VCR cell line. 1107 5

One of the proposed mechanisms for multidrug resistance relies on the ability of resistant tumor cells to efficiently promote glutathione S-transferase (GST)-catalyzed GSH conjugation of the antitumor drug. This type of conjugation, observed in several families of drugs, has never been documented satisfactorily for anthracyclines. Adriamycin-resistant human breast cancer MCF-7/DOX cells, presenting a comparable GSH concentration, but a 14-fold increase of the GST P1-1 activity relative to the sensitive MCF-7 cells, have been treated with adriamycin in the presence of verapamil, an inhibitor of the 170 P-glycoprotein (P-gp) drug transport protein, and scrutinized for any production of GSH-adriamycin conjugates. HPLC analysis of cell content and culture broths have shown unequivocally that no GSH conjugates are present either inside the cell or in the culture broth. The only anthracycline present inside the cells after 24 hr of incubation was > 98% pure adriamycin. Confocal laser scanning microscopic observation showed that in MCF-7/DOX cells adriamycin was localized mostly in the Golgi apparatus rather than in the nucleus, the preferred site of accumulation for sensitive MCF-7 cells. These findings rule out GSH conjugation or any other significant biochemical transformation as the basis for resistance to adriamycin and as a ground for the anomalous localization of the drug in the cell. Adriamycin, daunomycin, and menogaril did not undergo meaningful conjugation to GSH in the presence of GST P1-1 at pH 7.2. Indeed, their synthetic C(7)-aglycon-GSH conjugates exerted a strong inhibitory effect on GST P1-1, with K(i) at 25 degrees in the 1-2 microM range, scarcely dependent on their stereochemistry at C(7).
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PMID:Lack of glutathione conjugation to adriamycin in human breast cancer MCF-7/DOX cells. Inhibition of glutathione S-transferase p1-1 by glutathione conjugates from anthracyclines. 1110 8

Paclitaxel and carboplatin chemotherapy is reported to be a platelet-sparing drug combination. This study investigated potential mechanisms for this observation by studying the effects of paclitaxel and carboplatin on (1) normal donor and chemotherapy patient-derived erythroid (burst-forming units-erythroid [BFU-E]), myeloid (colony-forming units-granulocyte/macrophage [CFU-GM]), and megakaryocyte (CFU-Meg) progenitor cell growth; (2) P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) messenger RNA (mRNA) expression; (3) serum thrombopoietin (Tpo), stem cell factor (SCF), interleukin-6 (IL-6), IL-11, IL-1beta, IL-8, and tumor necrosis factor-alpha levels in patients treated with paclitaxel and carboplatin; and (4) stromal cell production of Tpo and SCF after paclitaxel and carboplatin exposure. CFU-Meg were more resistant to paclitaxel alone, or in combination with carboplatin, than CFU-GM and BFU-E. Although all progenitors expressed P-gp protein and GST mRNA, verapamil treatment significantly, and selectively, increased the toxicity of paclitaxel and carboplatin to CFU-Meg, suggesting an important role for P-gp in megakaryocyte drug resistance. Compared to normal controls, serum Tpo levels in patients receiving paclitaxel and carboplatin were significantly elevated 5 hours after infusion and remained elevated at day 7 (287% +/- 63% increase, P <.001). Marrow stroma was shown to be the likely source of this Tpo. It is concluded here that P-gp-mediated efflux of paclitaxel, and perhaps GST-mediated detoxification of carboplatin, results in relative sparing of CFU-Meg, which may then respond to locally high levels of stromal cell-derived Tpo. The confluence of these events might lead to the platelet-sparing phenomenon observed in patients treated with paclitaxel and carboplatin chemotherapy.
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PMID:Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy. 1115 79

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.
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PMID:Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100. 1117 67

The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.
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PMID:The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. 1129 49

Multidrug resistance is a major obstacle for the successful use of chemotherapy. The multidrug resistance phenotype is often attributed to overexpression of P-glycoprotein, which is an energy-dependent drug efflux pump. We investigated a new strategy to overcome multidrug resistance, using purified bovine serum amine oxidase, which generates two major toxic products from the polyamine spermine. The cytotoxicity of the aldehyde(s) and H2O2, produced by the enzymatic oxidation of micromolar concentrations of spermine, was evaluated in multidrug resistant Chinese hamster ovary cells CHRC5 with overexpression of P-glycoprotein, using a clonogenic cell survival assay. We examined the ability of hyperthermia (42 degrees C), and inhibition of cellular detoxification systems, to sensitize multidrug resistant cells to spermine oxidation products. Severe depletion of intracellular glutathione was achieved using L-buthionine sulfoximine and inhibition of glutathione S-transferase by ethacrynic acid. CH(R)C5 cells showed no resistance to the toxic oxidation products of spermine, relative to drug-sensitive AuxB1 cells. Exogenous catalase protected cells against cytotoxicity of H2O2, but spermine-derived aldehyde(s) still caused some cytotoxicity. Hyperthermia (42 degrees C) enhanced cytotoxicity of spermine oxidation products. Cytotoxic responses in CH(R)C5 cells were compared to the drug-sensitive cells, to determine whether there are differential responses. CH(R)C5 cells were more sensitive to the cytotoxic effect of spermine oxidation products under more extreme conditions (higher temperature, higher spermine concentration, and longer exposure time). Glutathione depletion or glutathione S-transferase inhibition also led to enhanced cytotoxicity of spermine oxidation products in CH(R)C5 and AuxB1 cells. Our findings suggest that hyperthermia, combined with toxic oxidation products generated from spermine and amine oxidase, could be useful for eliminating drug-sensitive and multidrug resistant cells.
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PMID:Amine oxidase, spermine, and hyperthermia induce cytotoxicity in P-glycoprotein overexpressing multidrug resistant Chinese hamster ovary cells. 1131 May 64

Recent work shows that long-term exposure to low levels of arsenite induces malignant transformation in a rat liver epithelial cell line. Importantly, these chronic arsenic-exposed (CAsE) cells also develop self-tolerance to acute arsenic exposure. Tolerance is accompanied by reduced cellular arsenic accumulation, suggesting a mechanistic basis for reduced arsenic sensitivity. The present study examined the role of xenobiotic export pumps in acquired arsenic tolerance. Microarray analysis of CAsE cells showed increased expression of the genes encoding for glutathione S-transferase Pi (GST-Pi), multidrug resistance-associated protein genes (MRP1/MRP2, which encode for the efflux transporter Mrp1/Mrp2) and the multidrug resistance gene (MDR1, which encodes for the efflux transporter P-glycoprotein). These findings were confirmed at the transcription level by reverse transcription-polymerase chain reaction and at the translation level by Western-blot analysis. Acquired arsenic tolerance was abolished when cells were exposed to ethacrynic acid (an inhibitor of GST-Pi), buthionine sulfoximine (a glutathione synthesis inhibitor), MK571 (a specific inhibitor for Mrps), and PSC833 (a specific inhibitor for P-glycoprotein) in dose-dependent fashions. MK571, PSC833, and buthionine sulfoximine markedly increased cellular arsenic accumulation. Consistent with a role for multidrug resistance efflux pumps in arsenic resistance, CAsE cells were found to be cross-resistant to cytotoxicity of several anticancer drugs, such as vinblastine, doxorubicin, actinomycin-D, and cisplatin, that are also substrates for Mrps and P-glycoprotein. Thus, acquired tolerance to arsenic is associated with increased expression GST-Pi, Mrp1/Mrp2 and P-glycoprotein, which function together to reduce cellular arsenic accumulation.
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PMID:Overexpression of glutathione S-transferase II and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. 1145 17

The ability of physical and pharmacological modulators to increase the cytotoxicity of melphalan was investigated in Chinese hamster ovary cells using a clonogenic cell survival assay. Hyperthermia has potential for use in cancer treatment, particularly as an adjuvant to chemotherapy or radiotherapy. Ethacrynic acid is a glutathione S-transferase inhibitor and also undergoes conjugation with glutathione. Interactions between hyperthermia (41-43 degrees C), ethacrynic acid and melphalan were evaluated in multidrug-resistant (CH(R)C5) cells with overexpression of P-glycoprotein (33.69-fold), and in drug-sensitive (AuxB1) cells. GST alpha was expressed at a higher level (3.65-fold) in CH(R)C5 cells than in sensitive cells, whereas levels of isoforms pi and mu were the same. GST pi was the most highly expressed isoform in the two cell populations. Ethacrynic acid was cytotoxic at elevated temperatures, while it caused little or no cytotoxicity at 37 degrees C. This effect occurred in drug-resistant and drug-sensitive cells, and attributes thermosensitizing properties to ethacrynic acid. Ethacrynic acid (20 microM) alone did not alter the cytotoxicity of melphalan at 37 degrees C. Hyperthermia potentiated drug cytotoxicity in cells, both with and without ethacrynic acid treatment. Ethacrynic acid could be useful in cancer treatment by acting as a thermosensitizer when combined with heat and by enhancing the cytotoxicity of melphalan at elevated temperatures. A major advantage arising from the use of regional hyperthermia is the ability to target drug cytotoxicity to the tumor volume. A useful finding is that ethacrynic acid, heat and/or melphalan are also effective against multidrug-resistant cells with overexpression of P-glycoprotein.
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PMID:Sensitization to the cytotoxicity of melphalan by ethacrynic acid and hyperthermia in drug-sensitive and multidrug-resistant Chinese hamster ovary cells. 1150 Jan 36

This work compares glutathione levels, glutathione S-transferase activities and isoenzyme expression, metallothionein levels and P-glycoprotein expression in normal ovaries, and in epithelial ovarian tumor biopsies from patients prior to chemotherapy or following relapse. These parameters have been implicated as determinants of response to cytotoxic chemotherapy. Large differences were found between normal ovary and ovarian tumors, but no significant differences were observed between tumors taken before or after cytotoxic chemotherapy. These data do not support a role for these biochemical parameters in the decreased response seen in patients with recurrent or progressive disease.
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PMID:Correlation of drug resistance-associated parameters in ovarian tumor biopsies. 1157 13

This study was planned to evaluate the prognostic role of glutathione S-transferase pi (GST-pi) and P-glycoprotein (P-gp) expressions in children with neuroblastoma. Sections from formalin-fixed paraffin-embedded tumor blocks from 52 neuroblastoma cases (17 with localized, 35 with advanced disease) were subjected to immunohistochemistry for P-gp and GST-pi expressions. The overall number of tumors positive for P-gp and GST-pi were 19 (36.5%) and 21 (40.4%), respectively. Twenty-two tumors were negative for both GST-pi and P-gp expressions, whereas 10 expressed both proteins. The distribution of staining status of samples in the groups of both proteins showed no significant difference. No relation between the expressions of both proteins and the clinical characteristics of the patients was demonstrable. The differenes between the survival rates of patients with positive and negative staining for P-gp expression were not statistically significant. Although 2 common mechanisms of multiple drug resistance, P-gp and GST-pi, might be responsible for drug resistance in neuroblastoma, this complex mechanism has no direct significant impact on prognosis. Multiple mechanisms at cellular levels are responsible for the resistance against antineoplastic therapies in neuroblastoma.
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PMID:Glutathione S-transferase and P-glycoprotein expressions in neuroblastoma. 1207 65


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