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 caused by P-glycoprotein (P-170) is a phenomenon by which cells exposed to a single drug acquire resistance to other structurally and functionally unrelated drugs. This is a widespread phenomenon described in vivo in the management of infectious as well as non-infectious diseases. Several in vitro models have been developed in order to evaluate physiopathological properties of P-170. Among these are P-170-expressing variants of the human T-lymphoblastoid CEM cell line called VBL100. As a general rule, drug resistance normally results in resistance to apoptosis induction. By contrast, a paradoxical activity is exerted in this cell model by the cytokine tumour necrosis factor-alpha (TNF-alpha), which is capable of inducing apoptosis in P-170-expressing variants better than in wild-type (wt) cells. In the present study we partially address the mechanisms underlying this activity. In fact, the susceptibility of VBL100 cells to TNF-alpha appears to be specifically due to the depolarization of their mitochondrial membrane, a key factor for apoptotic induction. The same was observed with staurosporine, a specific mitochondrion-mediated proapoptotic chemical probe. Conversely, other proapoptotic stimuli, such as Fas/CD95 or the anti-cancer drug etoposide, did induce significant cell death in wild type cells only. Thus, schematically, mitochondrially dependent stimuli appeared to be more effective in VBL100-cell killing, while 'physiological' stimuli showed the opposite behaviour. Importantly, under steady-state conditions, VBL100 cells displayed per se a mitochondrial membrane hyperpolarization that appeared strictly related to their high susceptibility to specific apoptotic stimuli. In conclusion, the study of a well-established cell model such as that represented by the wt/VBL CEM lymphoid cell line seems to suggest that the multidrug resistance phenotype can specifically sensitize cells towards 'unphysiological', mitochondria-associated cell death cascade or, in the same fashion, it could shift cells from type I (mainly plasma membrane-associated) towards type II (mainly mitochondrial membrane-associated) phenotype.
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PMID:Expression of P-170 glycoprotein sensitizes lymphoblastoid CEM cells to mitochondria-mediated apoptosis. 1131 Nov 19

The variability of P-glycoprotein expression between individuals is linked to a C3435T polymorphism of the human MDR1 gene. Concentration of P-glycoprotein in intestinal epithelial cells and in a subset of lymphoid cells is substantially lower in people with the T/T genotype than those with the C/C genotype. We compared allele frequencies of the C3435T polymorphism in random samples of west African, African American, white, and Japanese people. We recorded a significantly higher frequency of the C/C genotype in West Africans and African Americans (142 of 172 [83%] and 25 of 41 [61%], respectively), than in white people (139 of 537 [26%]) (p<0.0001). These findings could affect use of drugs that are P-glycoprotein substrates (such as HIV-1 protease inhibitors and ciclosporin) in African populations.
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PMID:Frequency of C3435T polymorphism of MDR1 gene in African people. 1180 18

Tc-99m sestamibi (MIBI) has been used as a tumor-seeking agent. However, its role in detecting lymphomas has not been widely investigated. The aim of the present study was to determine the uptake and clearance characteristics of Tc-99m MIBI in vincristine-resistant lymphoma cell lines. In addition, thallium-201 (Tl-201) and gallium-67 (Ga-67) uptake and clearance characteristics were evaluated for comparison with Tc-99m MIBI. Drug-resistant lymphoma cell lines (monocyte-like, histiocytic lymphoma, human; B-lymphoma cell line, American Burkitt lymphoma, lymphoblastoid, human; Hodgkin's disease, lymphoid, human) were selected by multistep vincristine treatment up to 50 nM. After incubation of the radiotracers, Tc-99m MIBI, Tl-201 and Ga-67, in medium for 0, 10, 20, 30, 60 or 120 min, the uptake and clearance of each radiotracer were measured in the drug-resistant lymphoma cell lines. In addition, P-glycoprotein expression was determined by immunohistochemical study. In a comparison of the three radiotracers, the uptake of Tc-99m MIBI was the greatest in the studied wild-type lymphoma cell lines. Tc-99m MIBI uptake was much lower in drug-resistant tumor cell lines than in non-resistant cell lines. On the other hand, the uptake characteristics of Tl-201 did not differ between drug-resistant and non-resistant cells. Immunohistochemistry analyses of Ab-1 or JSB indicated that tumor cells expressed MDR-1 protein in all three cell lines. Tc-99m MIBI is a good radiotracer for detecting drug resistance in lymphoma cell lines.
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PMID:Comparison of the uptake and clearance of Tc-99m MIBI, Tl-201 and Ga-67 in drug-resistant lymphoma cell lines. 1152 May 98

To better understand physiological function of P-glycoprotein (P-gp), encoded by MDR1 gene, and its role in cancer, we analyzed tumor and corresponding normal tissue from 400 patients with previously non treated colorectal cancer for germline and somatic alterations in MDR1 gene and compared the results to histopathological data and microsatellite instability status of tumors. We have identified naturally occurring mutations in the MDRI gene associated with colorectal cancers with high microsatellite instability (MSI-H) suggesting that tumor cells with MDR1 mutations are selected for during development of MSI-H cancers and that MDR1 plays an important role in tumor initiation and progression in at least a proportion of MSI-H cancers. We found that in all MSI-H tumors with MDR1 mutations, both, the coding and promoter regions were mutated. These results and results from others suggest that alterations in MDR1 promoter are important for P-gp function and that screening for naturally occurring mutations in the promoter region of MDR1 is important in some of the human cancers. We have identified also 12 different germline polymorphisms and at least two of them were significantly associated with increased lymphoid infiltration in tumors suggesting physiological function for P-gp in immune response in addition to protection from xenobotics.
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PMID:The role of P-glycoprotein (MDR1) polymorphisms and mutations in colorectal cancer. 1167 32

P-glycoprotein is a 170-kd glycosylated transmembrane protein, expressed in a variety of human cells and belonging to the adenosine triphosphate-binding cassette transporter family, whose membrane expression is functionally associated with the multidrug resistance phenotype. However, the mechanisms underlying the regulation of P-glycoprotein functions remain unclear. On the basis of some evidence suggesting P-glycoprotein-actin cytoskeleton interaction, this study investigated the association of P-glycoprotein with ezrin, radixin, and moesin, a class of proteins that cross-link actin filaments with plasma membrane in a human cell line of lymphoid origin and that have been shown to link other ion-pump-related proteins. To this purpose, a multidrug-resistant variant of CCRF-CEM cells (CEM-VBL100) was used as a model to investigate the following: (1) the cellular localizations of P-glycoprotein and ezrin, radixin, and moesin and their molecular associations; and (2) the effects of ezrin, radixin, and moesin antisense oligonucleotides on multidrug resistance and P-glycoprotein function. The results showed that: (1) P-glycoprotein colocalized and coimmunoprecipitated with ezrin, radixin, and moesin; and (2) treatment with antisense oligonucleotides for ezrin, radixin, and moesin restored drug susceptibility consistently with inhibition of both drug efflux and actin-P-glycoprotein association and induction of cellular redistribution of P-glycoprotein. These data suggest that P-glycoprotein association with the actin cytoskeleton through ezrin, radixin, and moesin is key in conferring to human lymphoid cells a multidrug resistance phenotype. Strategies aimed at inhibiting P-glycoprotein-actin association may be helpful in increasing the efficiency of both antitumor and antiviral therapies.
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PMID:P-glycoprotein-actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin. 1178 Dec 49

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

A small but significant fraction of pemphigus patients do not show an adequate response to steroid therapy. P-glycoprotein (or P-gp) is a cell membrane efflux pump that expels drugs, including glucocorticoids, from the cytosol to the extracellular medium. An increased expression and/or function of P-glycoprotein in lymphoid cells could decrease the intracellular concentration of glucocorticoids, diminishing its therapeutic effects. The aim of this work was to assess the expression and activity of P-glycoprotein in the mononuclear cells (MNC) from pemphigus patients with good and poor response to steroid therapy. We studied 20 patients with pemphigus vulgaris, eight of them classified as poor responders and 12 as good responders to steroid therapy. The expression and activity of P-glycoprotein by MNC were quantified by flow cytometry, and P-glycoprotein mRNA levels were determined by a semi-quantitative RT-PCR technique. We found that the expression of P-glycoprotein at both mRNA and protein levels was similar in pemphigus patients with good and poor response to steroid therapy. Similar results were obtained regarding P-glycoprotein activity. P-glycoprotein does not seem to be involved in the poor response to steroid treatment seen in some pemphigus patients. It is important to investigate additional mechanisms that could account for the glucocorticoid resistance seen in some pemphigus patients.
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PMID:Lack of involvement of P-glycoprotein (P-gp) in pemphigus patients with poor response to steroid therapy. 1191 9

Multidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct post-transcriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naive cells (not exposed to drugs) was stabilized (half-life greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct P-glycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steady-state MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic.
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PMID:P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation. 1252 96

Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor/lymphoid enhancer factor complex has been considered crucial for the initiation of intestinal tumorigenesis. The human multidrug resistance (MDR)1 (ABCB1) gene contains multiple beta-catenin-T-cell factor4-binding elements in its promoter and is one of the immediate targets of the complex. In the current study, we have further substantiated the biological involvement of MDR1 in intestinal tumorigenesis based on the following evidence: (a) aberrant induction of the Mdr1a (Abcb1a) gene product, P-glycoprotein, associated with nuclear accumulation of the beta-catenin protein, was observed even in nascent microscopic adenomas of Min mice; (b) Mdr1-deficient Min (Apc(Min/+)Mdr1a/b(-/-)) mice developed significantly fewer intestinal polyps than did Apc(Min/+)Mdr1a/b(+/+) mice; and (c) Inhibitors of P-glycoprotein, verapamil, and cyclosporin A had a suppressive effect on the in vitro polypoid growth of IEC6 expressing stabilized (DeltaN89) beta-catenin protein. Inhibitors of P-glycoprotein may be included in a novel class of chemopreventive agents against colorectal carcinogenesis.
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PMID:Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice. 1261 99

Miltefosine is a phospholipid analog that exhibits antineoplastic activity against breast cancer metastases, but its mechanism of action remains uncertain. The aim of this study was to investigate the transport mechanism for the removal of miltefosine and [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) from multidrug-resistant cells. The P-glycoprotein pump function, cell viability, and 99mTc-MIBI and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) uptakes were measured in NIH 3T3 (3T3) and NIH 3T3MDR1 G185 (3T3MDR1) mouse fibroblasts and human lymphoid B JY cells. Miltefosine treatment increased the permeability and fluidity of these tumor cells in a concentration-dependent manner. The multidrug-sensitive cells were 3-4 times more sensitive to miltefosine than the multidrug-resistant ones. The extent of 99mTc-MIBI accumulation in the P-glycoprotein-expressing cells increased in the presence of miltefosine, whereas the rhodamine123 and daunorubicin uptakes of the cells did not change significantly. In the 3T3MDR1 cells verapamil reinstated the rhodamine123 and daunorubicin accumulation, but not the 99mTc-MIBI uptake. Cyclosporin A reinstated the uptakes of 99mTc-MIBI, daunorubicin and rhodamine123 by the 3T3MDR1 cells. In a concentration-dependent manner miltefosine decreased the extents of 99mTc-MIBI, rhodamine123, daunorubicin and 18FDG accumulation in the JY and 3T3 cells. Our findings indicate a common transport mechanism for 99mTc-MIBI and miltefosine, which is distinct from that for rhodamine123 and daunorubicin in MDR cells.
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PMID:Effects of miltefosine on membrane permeability and accumulation of [99mTc]-hexakis-2-methoxyisobutyl isonitrile, 2-[18F]fluoro-2-deoxy-D-glucose, daunorubucin and rhodamine123 in multidrug-resistant and sensitive cells. 1578 39


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