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)

The emergence of drug resistance is a major obstacle to effective cancer chemotherapy. The identification of novel agents that serve as selective, potent and nontoxic modulators of drug resistance is thus an important goal for improving the success of cancer treatment. Thaliblastine (TBL), a plant alkaloid and P-glycoprotein (P-gp) inhibitor, is presently shown to fully reverse 490-fold resistance to Adriamycin (AdR) in a multidrug-resistant (MDR) human breast cancer cell line (MCF/AdR) that overexpresses P-gp, whereas the same treatment had no effect on AdR cytotoxicity in the drug-sensitive parental MCF-7 cells. Mechanistic studies showed that this striking resistance reversal was achieved without alteration of cellular levels of glutathione and without inhibition of glutathione S-transferase, glutathione peroxidase or P450 reductase by TBL, each of which is significantly altered in MCF/AdR cells, and each of which has been proposed to contribute to AdR resistance in this MDR line. Rather, resistance reversal by TBL can be entirely explained by this drug's capacity to restore the intracellular accumulation of AdR in the resistant cells. These results establish that MDR associated with P-gp overexpression can be fully reversed by the potent P-gp inhibitor TBL. They further indicate that although changes in multiple drug-metabolizing enzymes may accompany the development of MDR, these multiple biochemical alterations need not correspond to multiple functional determinants for drug resistance.
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PMID:Complete reversal by thaliblastine of 490-fold adriamycin resistance in multidrug-resistant (MDR) human breast cancer cells. Evidence that multiple biochemical changes in MDR cells need not correspond to multiple functional determinants for drug resistance. 756 98

Tumor tissues of untreated and cytostatic-agent-treated patients with nephroblastomas were investigated for expression of resistance-related proteins (P-glycoprotein, glutathione S-transferase-pi, glutathione peroxidase and topoisomerase II) to ascertain whether resistance proteins are changed after treatment. Tumor tissue was analyzed by means of mRNA. Twenty-three children were treated with actinomycin D and vincristine for 4 to 8 weeks. Eight children received no preoperative chemotherapy. In untreated patients, no expression of P-glycoprotein was seen, whereas, in the patients who were treated with actinomycin D and vincristine, 12 out of 23 tumors showed increased P-glycoprotein expression (> mean value). Although we found no difference between treated and untreated tumors for glutathione S-transferase-pi, we found significant differences in the expression of glutathione peroxidase. In the 8 untreated patients, 7 tumors showed low glutathione peroxidase (< mean value) and one high (> mean value) glutathione-peroxidase-mRNA content. With treatment, 11 tumors expressed low levels and 12 tumors high levels of mRNA. A significant positive correlation between P-glycoprotein and glutathione peroxidase was found. In addition, of the 8 untreated patients, 2 had low topoisomerase-II expression, and 6 high expression. With treatment, the expression was reduced in 18 tumors, and only 5 tumors had high levels of this protein. These results were confirmed by PCR and immunohistochemistry.
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PMID:Expression of resistance-related proteins in nephroblastoma after chemotherapy. 759 Dec 3

The levels of several potential indicators of resistance to cytostatic drugs were measured in leukaemic cells of a total of 64 adult patients with acute or chronic leukaemias before and during treatment and at relapse or recurrence of disease and compared with those of mononuclear cells from the bone marrow of healthy donors. The resistance factors included glutathione (GSH) and its associated enzymes glutathione-S-transferase (GST) and glutathione peroxidase (GPx) as well as O6-alkyguanine-DNA-alkyltransferase (ATase) and P-glycoprotein. Median values for most parameters were significantly higher in leukaemic cells than in those of normal donors although wide interindividual variation in the values of the various parameters, particularly GST, were seen. P-glycoprotein was measurable in 12.5% of untreated leukaemias but in none of the normal donors. The values of the parameters in untreated leukaemic patients were not statistically different from those at relapse or during disease progression. However, the median values for GSH, GST and GPx but not ATase in samples from untreated patients were significantly higher than those in samples taken during drug treatment. Patient response, disease-free survival or duration of remission did not correlate with the values of any of the parameters studied.
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PMID:Cytostatic drug resistance: parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA-alkyltransferase and P-glycoprotein in adult patients with leukaemia. 790 32

Resistance may limit the clinical usefulness of a variety of chemotherapeutic drugs including mitomycin C (MMC). The MMC-sensitive HT-29 colon cancer cell line and its MMC-resistant subline, HT-29R13, were studied in vitro under aerobic conditions to help characterize the mechanisms associated with MMC resistance. HT-29R13 cells exhibit approximately 2-fold resistance to MMC compared with HT-29 cells and lack the typical multidrug-resistance pattern; resistance is stable in the absence of drug exposure. Levels of glutathione (GSH) and total glutathione-S-transferase (GST) activity were not different between the two cell lines; however, levels of GSH reductase and GSH peroxidase were increased significantly in HT-29R13. Although total GST activity was unchanged, GST-pi and GST-alpha isoenzyme expression as measured using western blot were increased significantly in HT-29R13 compared with HT-29. DT-diaphorase levels and topoisomerase II activity were decreased significantly in HT-29R13. Both cell lines had equal P-glycoprotein expression. Multiple drug resistance mechanisms are present in HT-29R13 including decreased drug activation (decreased DT-diaphorase), increased drug detoxification (increased GST-pi and GST-alpha, GSH reductase, GSH peroxidase), and decreased accessibility of DNA targets (decreased topoisomerase II). Further work will be necessary to determine the degree to which each of these mechanisms contribute to MMC resistance in this model.
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PMID:Biochemical characterization of a mitomycin C resistant colon cancer cell line variant. 790 34

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.
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PMID:Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. 796 Feb 35

Small cell lung cancer (SCLC) is treated primarily with combination chemotherapy. Despite high initial response rates, most patients eventually die with drug resistant disease. In some tumours, resistance to multiple chemotherapeutic agents is attributed to overexpression of P-glycoprotein (P-gp). However, this does not appear to be a frequent occurrence in drug resistant SCLC. Increased levels of glutathione (GSH) and related enzymes may play a role in resistance to alkylating agents as well as natural product drugs. We measured levels of GSH, glutathione S-transferase (GST), glutathione reductase (GSH Red), glutathione peroxidase (GSH Px), and gamma-glutamyl transpeptidase (gamma-GT) in a panel of 20 SCLC cell lines. Most of these lines were established from patients treated at this centre. Each cell line had a characteristic and reproducible profile of GSH and related enzyme levels. Immunoblot analysis indicated that the predominant GST in the cell lines was the anionic pi isoenzyme. The relative sensitivity of each of these cell lines to 16 different chemotherapeutic agents was measured using a modified MTT assay. Spearman rank correlation analysis was used to determine the relationships between the relative chemosensitivity of these cell lines and the levels of GSH and related enzymes. The number of positive correlations was no greater than expected by chance alone. Furthermore, there was no correlation with the treatment history of the patients from whom the cell lines were derived. These data suggest that alterations in glutathione metabolism do not play a major role in resistance to chemotherapeutic agents in these human SCLC cell lines.
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PMID:Do glutathione and related enzymes play a role in drug resistance in small cell lung cancer cell lines? 810 44

We have previously established Adriamycin-resistant HOB1 cell lines showing the multidrug resistance (MDR) phenotype. For further study, we analyzed the free-radical scavengers glutathione S-transferase (GST) and glutathione peroxidase (GPX) by enzyme assays and Northern blots. Three cell lines, HOB1/ADR0.1, HOB1/ADR1.0, and HOB1/ADR5.0, represented HOB1 cells resistant to 0.1, 1.0, and 5.0 microM Adriamycin, respectively. The mdr1 transcript was overexpressed in HOB1/ADR0.1 cells, and the amount of its expression reached a maximum between HOB1/ADR1.0 and HOB1/ADR5.0 cell lines. The increases in GST activity and GST-pi expression were observed only in high-level-resistant cell line (HOB1/ADR1.0 and HOB1/ADR5.0), which also showed increased GPX activity and expression. For investigation of the cytotoxic effect of Adriamycin on HOB1 cells prior to the mdr1 overexpression, an appropriate number of parental HOB1 cells were treated with 0.1 microM Adriamycin for 7 days, and the viable cells (HOB1/ADR) were isolated and subjected to analyses for mdr1, GST-pi, and GPX expression and for GST and GPX activity. In comparison with HOB1/ADR0.1 cells, HOB1/ADR cells did not show mdr1 overexpression but had significant increases in the activity and expression of GST and GPX. The current study suggests that in the early phase of Adriamycin treatment, GST and GPX are more important than P-glycoprotein for the development in HOB1 cells of resistance against Adriamycin.
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PMID:Glutathione S-transferase and glutathione peroxidase are essential in the early stage of adriamycin resistance before P-glycoprotein overexpression in HOB1 lymphoma cells. 860 51

A certain percentage of cancers are primarily or subsequently resistant to chemetherapeutic agents. Several biological mechanisms are implicated in this phenomenon, including multidrug resistance/P-glycoprotein (mdr1/P-gp), resistance related proteins (P-95 and P-110), multidrug resistance associated protein (P-190), iso-enzymes of gluthatione S-transferase, topo-isomerases, glutathione peroxidase and others. mdr1/P-gp overexpression has been studied in many types of cancer. It represents an inducible, transferable and phylogenetically ancestral biological system. It is expressed at the surface of the cell, and in that way, it participates to several normal functions. The recent introduction of modulators/revertants of mdr1/P-gp may change some concepts in using chemotherapy for cancers. The first step is represented by a better knowledge of the cancers which overexpressed mdr1/P-gp, with determination of the best biological technique, including the gold standards. This allows the clinician to clarify the best impact of such a therapeutic way and to define the criteria of modulator selection. Such criteria includes in vitro selection using a panel of sensitive/resistant cell lines, in vivo tests including transgenic mice, nude or SCID mice, and toxicological studies. Choice of modulated drug is easier and depends on the biological target. For mdr1/P-gp, major drugs included doxorubicin and vinca-alkaloids. Due to the fact that some modulators have an influence on the pharmacokinetic parameters of chemotherapeutic drugs, it is important to verify such parameters. The last choice concerns the strategy of drug development with three levels of action: 1) modulation of clinical chemoresistance, intrinsic or acquired one; 2) modulation of biological resistance; 3) leading to the prevention of the amplification of low levels of chemoresistance. A new therapeutic way is born, which takes care of a dynamic aspect of the tumor, and necessitates a new use of chemotherapy.
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PMID:[Modulation of chemoresistance: methodology of therapeutic trials]. 873 92

A hydroquinone-resistant derivative of the M1 cell line, designated M1HQ, was generated and used to evaluate the biochemical mechanism responsible for resistance to oxidative stress-inducing agents. The hydroquinone concentrations that were cytotoxic to 50 and 90% of the parental M1 cell line in 48 hr were 25 and 90 microM, respectively, whereas exposure to 500 microM hydroquinone did not decrease M1HQ viability significantly. M1HQ cells grew slower than M1 cells and exhibited significantly higher resistance to colchicine, doxorubicin, hydrogen peroxide, 4-hydroperoxycyclophosphamide, and 1,3-bis (2-chloroethyl)-1-nitrosourea but not to benzoquinone, vinblastine, or gamma-radiation. M1HQ cells possessed significantly higher levels of total thiols, glutathione, glutathione peroxidase, glutathione reductase, quinone reductase, and gamma-glutamyl transpeptidase than the parental M1 cell line. Steady-state gamma-glutamylcysteine synthetase mRNA expression also was 1.6-fold higher in M1HQ cells. P-glycoprotein transcripts were detectable in both M1 and M1HQ cells, but were 2-fold higher in M1HQ. Multidrug resistance-associated protein transcripts were not detectable in either M1 or M1HQ. Hydroquinone resistance in M1HQ cells was partially reversible with a combination of inhibitors of quinone reductase, gamma-glutamylcysteine synthetase, glutathione peroxidase, and the multidrug resistance-associated protein, but not with inhibitors of P-glycoprotein, gamma-glutamyl transpeptidase, or glutathione-S-transferase. When treated with [14C]hydroquinone, M1HQ cells did not generate significant hydroquinone-protein adducts but did release an adduct similar to N-acetylcysteinyl-benzoquinone. In contrast, numerous [14C]hydroquinone-protein adducts were produced in M1 cells, while the N-acetylcysteinyl-benzoquinone-like molecule was undetectable. Thus, hydroquinone resistance in M1HQ cells appeared to result from a glutathione-dependent detoxification and export mechanism.
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PMID:Hydroquinone resistance in a murine myeloblastic leukemia cell line. Involvement of quinone reductase and glutathione-dependent detoxification in nonclassical multidrug resistance. 878 15

A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to multiple antitumor drugs, including mitomycin C (MMC) and porfiromycin (PFM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overexpression of P-glycoprotein (PGP), an increase in glutathione S-transferase activity, and a decrease in DT-diaphorase and glutathione peroxidase activity. The resistance to MMC and VLB of AH130/5A cells was partly reversed by H-87, an inhibitor of PGP. Buthionine sulfoximine, an inhibitor of glutathione synthase, did not affect the action of MMC. tert-Butylhydroquinone induced DT-diaphorase activity, increased PFM uptake, and enhanced the growth-inhibitory action of MMC in AH130/5A cells. Dicumarol, an inhibitor of DT-diaphorase, decreased PFM uptake and reduced the growth-inhibitory action of MMC in AH130/P cells. These results indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT-diaphorase activity.
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PMID:Establishment by adriamycin exposure of multidrug-resistant rat ascites hepatoma AH130 cells showing low DT-diaphorase activity and high cross resistance to mitomycins. 904 1


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