Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The identification of biologic markers for disease outcome in hematopoietic malignancies is essential for the development of "risk-adapted" therapies. Although new prognostic factors are frequently described, their real clinical and biologic impact is often difficult to determine. Factors that influence a marker's true prognostic value include several variables of study design: study size, uniform versus nonuniform patient treatment, methodologic variations, and correlations with other variables. Despite these concerns, several important prognostic factors have emerged in acute leukemias. For example, in acute myeloid leukemia, the multidrug resistant phenotype, whether conferred by the classic P-glycoprotein (multidrug resistance protein 1) or by other mechanisms, and cytogenetics are major prognostic indicators for outcome. In acute lymphoblastic leukemia, markers associated with loss of growth control (loss of tumor suppressor genes, increased proliferative fraction) likewise identify a group of poor-prognosis patients. The delineation of prognostic factors such as these allows for the better identification of patients who may benefit from risk-adapted therapies.
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PMID:Prognostic markers in acute leukemia. 937 96

ABC transporters are key players in the multidrug resistance of cancer cells and yeast, and they appear to be involved in the drug resistance of various pathogenic protozoa. No member of this ubiquitous protein family has yet been described in Trypanosoma brucei spp., the causative agents of African sleeping sickness and animal trypanosomiases. However, different cases of artificially induced drug resistance were shown to be linked to a reduction in net drug uptake. We used polymerase chain reaction with degenerate oligonucleotide primers corresponding to particularly conserved regions within the ATP-binding cassette to probe the genome of T. brucei spp. for the presence of ABC transporter genes. Three different sequence segments encoding ATP-binding cassettes were identified, which, upon Southern blotting, appeared to belong to distinct genes designated Tbabc1, Tbabc2, and Tbabc3. They appear to be single-copy genes in both drug-susceptible and drug-resistant stocks of T. brucei spp., expressed in bloodstream forms as well as in the procyclic life stage. Whereas Tbabc3 shows moderate homology to various known ABC transporters, Tbabc1 and Tbabc2 are highly homologous to P-glycoprotein A of Leishmania tarentolae and to the multidrug resistance protein 1 of L. donovani, respectively.
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PMID:Identification of three ABC transporter genes in Trypanosoma brucei spp. 949 8

To develop a functional assay for the activity of the multidrug resistance protein 1 (MRP1), we tested whether carboxyfluorescein (CF) was specifically transported by MRP and whether this transport pump could be specifically blocked by the leukotriene D4 receptor antagonist MK-571. The activity and expression of MRP1 were studied in several tumor cell lines and in leukemic blasts from patients with acute myeloid leukemia (AML). In the MRP1-overexpressing cell line GLC4/ADR and the MRP1-transfected cell line S1(MRP), MK-571 inhibited CF efflux with high factors [45.9+/-5.8 (mean+/-SD) and 14.4+/-3.2, respectively; n=3; efflux-blocking factors are defined as the ratio of the median fluorescence in presence or absence of MK-571] compared with their MRP1 low-expressing counterparts GLC4 (11.5+/-2.7) and S1 (2.8+/-0.4). In 15 AML cases, the CF efflux-blocking factors of MK-571 varied between 1.9 and 5.2. A good correlation was found between MRP1 protein expression and CF efflux-blocking factors of MK-571 (P=0.013, r=0.39). Besides MRP1, MRP2 was demonstrated with reverse transcription-PCR in 40% of the cases. In contrast to the cell lines, MK-571 also inhibited rhodamine 123 (Rh123) efflux in AML samples. On the other hand, PSC833, a P-glycoprotein specific inhibitor, did not modulate the CF efflux but is efficient in blocking Rh123 efflux. This study demonstrates that AML blasts express MRP1 and MRP2 and that MRP1 activity can be determined by a flow cytometric assay using CF and MK-571.
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PMID:Activity and expression of the multidrug resistance proteins MRP1 and MRP2 in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells. 967 48

Multidrug resistance in tumor cells is often associated with reduced drug accumulation resulting from increased expression of the 190-kDa multidrug resistance protein 1 (MRP1) or the 170-kDa P-glycoprotein. However, unlike P-glycoprotein, MRP1 is a primary active transporter of many conjugated organic anions, including the cysteinyl leukotriene LTC(4). Moreover, agents such as verapamil that reverse P-glycoprotein-mediated resistance are often poorly, or not at all, effective in MRP1-overexpressing cells. In the present study, we investigated the effects of verapamil on MRP1-mediated transport processes. We found that verapamil inhibited LTC(4) transport into inside-out membrane vesicles prepared from MRP1-transfected cells in a competitive manner, but only in the presence of reduced glutathione (GSH) or its nonreducing S-methyl derivative. In the presence of 1 mM GSH, the apparent K(i) for verapamil was 1.2 microM, and in the presence of 100 microM verapamil, the apparent K(i) for GSH was 77 microM. Verapamil itself was not transported by MRP1 in either intact cells or membrane vesicles. However, verapamil strongly stimulated MRP1-mediated GSH uptake by membrane vesicles in a concentration-dependent and osmotically sensitive manner that was inhibitable by MRP1-specific monoclonal antibodies. In the presence of 100 microM verapamil, the apparent K(m) and V(max) for GSH uptake were 83 microM and 55 pmol mg(-1) min(-1), respectively. It is proposed that the variable ability of verapamil to modulate MRP1-mediated resistance in different cell lines may be more closely linked to its effect on the GSH status of the cells than on its ability to inhibit the MRP1 transporter itself.
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PMID:Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). 1077 25

Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (MDRI) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported solely using mRNA data. In this study, we describe a BCRP-specific monoclonal antibody, BXP-34, obtained from mice, immunized with mitoxantrone-resistant, BCRP mRNA-positive MCF-7 MR human breast cancer cells. BCRP was detected in BCRP-transfected cells and in several mitoxantrone- and topotecan-selected tumor cell sublines. Pronounced staining of the cell membranes showed that the transporter is mainly present at the plasma membrane. In a panel of human tumors, including primary tumors as well as drug-treated breast cancer and acute myeloid leukemia samples, BCRP was low or undetectable. Extended studies will be required to analyze the possible contribution of BCRP to clinical multidrug resistance.
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PMID:Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines. 1082 26

Failure of chemotherapy is frequently observed in patients previously treated with radiotherapy. To establish a cellular model for examining this resistance phenotype a series of mammalian tumor cell lines were exposed in vitro to fractionated X-irradiation and were then shown to express resistance to multiple antitumor drugs, including vincristine, etoposide and cisplatin. In these experiments the radiation was delivered as 10 fractions of 5 Gy (dose resulting in 1 log cell kill) given intermittently over several months. We now report that a comparable multidrug-resistance profile is expressed by human SK-OV-3 human ovarian tumor cells exposed in vitro to low dose (2 Gy) twice-daily fractions of X-rays given for 5 days on two consecutive weeks, essentially mimicking clinical practice, involving an overexpression of two MDR-associated proteins, P-glycoprotein and the multidrug resistance protein 1 (MRP1), with the latter being readily detectable by immunocytochemistry.
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PMID:Low-dose twice-daily fractionated X-irradiation of ovarian tumor cells in vitro generates drug-resistant cells overexpressing two multidrug resistance-associated proteins, P-glycoprotein and MRP1. 1083 Dec 78

Two prominent members of the ATP-binding cassette superfamily of transmembrane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug resistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotics and (anticancer) drugs from normal and tumor cells. The MRP subfamily consists of at least six members, and here we report the functional characterization of human MRP5. We found resistance against the thiopurine anticancer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in MRP5-transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the cells that overproduce MRP5. In polarized Madin-Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is routed to the basolateral membrane and these cells transport S-(2,4-dinitrophenyl)glutathione and glutathione preferentially toward the basal compartment. Inhibitors of organic anion transport inhibit transport mediated by MRP5. We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.
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PMID:Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. 1084 50

We have obtained a novel multidrug resistant cell line, derived from HT29 G(+) human colon carcinoma cells, by selection with gradually increasing concentrations of the anti-mitotic, microtubule-disrupting agent colchicine. This HT29(col) cell line displayed a 25-fold increase in colchicine resistance and exhibited cross-resistance to doxorubicin, VP16, vincristine and taxol. Immunoblotting, combined with RT-PCR showed that the multidrug resistance phenotype was conferred by specific overexpression of the multidrug resistance protein 1. Confocal scanning laser microscopy revealed that multidrug resistance protein 1 specifically localized in the plasma membrane of HT29(col) cells. In a functional assay, using the fluorescent multidrug resistance protein 1 substrate 5-carboxyfluorescein, an increased efflux activity of HT29(col) cells was measured, as compared to the wild-type HT29 G(+) cells. MK571, a specific inhibitor of multidrug resistance protein 1, blocked the 5-carboxyfluorescein efflux, but only partially reversed resistance to colchicine, indicating that additional multidrug resistance mechanisms operate in HT29(col) cells. In conclusion, these results show for the first time overexpression of a functional multidrug resistance protein 1 under colchicine pressure, indicating that colchicine is not a P-glycoprotein-specific substrate. Colchicine-induced overexpression of multidrug resistance protein 1 is accompanied by a changed sphingolipid composition, i.e., enhanced levels of glucosylceramide and galactosylceramide. In addition, ceramide, a lipid messenger molecule involved in apoptosis-related signal transduction processes, was much more abundant in HT29(col) cells, which is indicative of a stress response.
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PMID:Differential expression of sphingolipids in MRP1 overexpressing HT29 cells. 1086 70

Tumor cells may display a multidrug resistance phenotype by overexpression of ATP binding cassette transporter genes such as multidrug resistance (MDR) 1 P-glycoprotein (P-gp) or the multidrug resistance protein 1 (MRP1). MDR3 P-gp is a close homologue of MDR1 P-gp, but its role in MDR is probably minor and remains to be established. The MRP1 protein belongs to a family of at least six members. Three of these, i.e., MRP1, MRP2, and MRP3, can transport MDR drugs and could be involved in MDR. The substrate specificity of the other family members remains to be defined. Specific monoclonal antibodies are required for wide-scale studies on the putative contribution of these closely related transporter proteins to MDR. In this report, we describe the extensive characterization of a panel of monoclonal antibodies (Mabs) detecting several MDR-related transporter proteins in both human and animal tissues. The panel consists of P3II-1 and P3II-26 for MDR3 P-gp; MRPr1, MRPm6, MRPm5, and MIB6 for MRP1; M2I-4, M2II-12, M2III-5 and M2III-6 for MRP2; M3II-9 and M3II-21 for MRP3; and M5I-1 and M5II-54 for MRP5. All Mabs in the panel appeared to be fully specific for their cognate antigens, both in Western blots and cytospin preparations, as revealed by lack of cross-reactivity with any of the other family members. Indeed, all Mabs were very effective in detecting their respective antigens in cytospins of transfected cell lines, whereas in flow cytometric and immunohistochemical analyses, distinct differences in reactivity and suitability were noted. These Mabs should become valuable tools in studying the physiological functions of these transporter proteins, in screening procedures for the absence of these proteins in hereditary metabolic (liver) diseases, and in studying the possible contributions of these molecules to MDR in cancer patients.
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PMID:Specific detection of multidrug resistance proteins MRP1, MRP2, MRP3, MRP5, and MDR3 P-glycoprotein with a panel of monoclonal antibodies. 1101 57

Transporters such as P-glycoprotein (MDR1), multidrug resistance protein 1 (MRP1), lung resistance-related protein (LRP) and breast cancer resistance protein (BCRP) are associated with multidrug resistance in various carcinoma cell lines. The expression of these molecules has been also characterized in human normal tissues. However, the expression of these molecules in oocyte is still unclear. In order to obtain more insight into the physiological role of these transporters, their expression in porcine oocyte were examined by reverse transcriptase-polymerase chain reaction. MDR1, MRP1 and LRP genes, but not BCRP gene were found to be expressed in porcine oocyte. After the subcloning and sequence analysis of MDR1, MRP1 and LRP genes, the high homology of these transporters were observed between porcine and human gene. These findings suggest that MDR1, MRP1 and LRP play an important physiological role(s) in an oocyte.
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PMID:Expression of multidrug resistance associated transporters (MDR1, MRP1, LRP and BCRP) in porcine oocyte. 1125 80


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