Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three newly synthesized imidazothiazole derivatives (N276-12, N276-14, N276-17) were examined regarding their ability and mechanism as a chemosensitizing agent against multidrug resistance 1 (MDR1)-mediated and multidrug resistance-associated protein (MRP)-mediated MDR. All three N276 compounds almost completely reversed the acquired resistance to vincristine (VCR), vinblastine (VBL), and doxorubicin (DXR) in MDR1-overexpressing human cancer cell lines (KB/VJ300 and T24/VCR). Their reversal effect against acquired resistance to VCR, DXR, and etoposide (VP16) was partial but clearly observed in the cell line expressing MRP (KB/VP4). All three N276 compounds enhanced the intracellular accumulation of [3H]VCR in MDR1-overexpressing KB/VJ300 cells through the inhibition of the increased efflux of the drug. They (100 microM) almost completely inhibited the photoaffinity labeling of P-glycoprotein encoded by the MDR1 gene. All the N276 compounds also remarkably enhanced the sensitivity to VBL and DXR in both MDR1- and MRP-overexpressing renal cell carcinoma (RCC) cell line (NKK1), whereas they showed no potentiation of these anticancer agents in an RCC cell line (KPK1) expressing neither MDR1 nor MRP. The combination chemotherapy of VCR or VP16 with N276-12 significantly increased the life span of mice inoculated i.p. or i.v. with drug-resistant P388/VCR cells without any significant side effects, whereas chemotherapy with the anticancer agent alone did not increase the life span at all. These results suggest that these newly synthesized imidazothiazole derivatives can be a useful chemosensitizing agent against not only MDR1- but also MRP-mediated MDR.
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PMID:Development of novel reversal agents, imidazothiazole derivatives, targeting MDR1- and MRP-mediated multidrug resistance. 970 Jul 23

Kaposi's sarcoma (KS) is considered a disorder of cytokines. Basic fibroblast growth factor (bFGF) is produced by AIDS-associated KS (AIDS-KS) cells and supports their growth in an autocrine and paracrine manner. bFGF lacks a signal sequence; therefore, its mechanism of secretion is unclear. In this study, we investigate the role of two important members of ATP-binding cassette transport proteins, the P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), in the secretion of bFGF from AIDS-KS cells. Expression of P-gp and MRP was examined at both the protein and the mRNA levels by flow cytometry and RT-PCR respectively. Intracellular and secreted bFGF was measured by ELISA. AIDS-KS cells expressed MRP at both the mRNA and the protein levels; however, no P-gp expression was detected at either the mRNA or the protein level. Probenecid, a putative inhibitor of MRP efflux function, in a concentration-dependent manner, inhibited bFGF secretion, with a concomitant increase in intracellular bFGF, demonstrating that probenecid blocks bFGF secretion without inhibiting its synthesis. In addition, probenecid induced apoptosis in AIDS-KS cells. AIDS-KS cells expressed fas, bcl-2, and bcl-xL genes but lacked fasL and bax gene expression. These data suggest that bFGF is secreted from AIDS-KS cells via a probencid-sensitive transporter, most likely in MRP. Furthermore, probenecid appears to induce apoptosis in AIDS-KS cells by depriving them of the growth promoting activity of bFGF. These data suggest that MRP may play a role as a survival molecule in AIDS-KS cells.
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PMID:A possible role of multidrug resistance-associated protein (MRP) in basic fibroblast growth factor secretion by AIDS-associated Kaposi's sarcoma cells: a survival molecule? 971 Jul 42

To address a possible impairment of multidrug resistance mechanisms in acquired aplastic anaemia (AA), the functions of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) were respectively assessed by rhodamine 123 (Rh123) and daunorubicin (DNR) efflux in peripheral blood lymphocytes from AA patients. The proportion of Rh123-effluxing T cells was significantly decreased in AA, relative to controls. Interestingly, these changes were also present in patients with AA in remission. Conversely, Rh123 efflux in B and natural killer (NK) cells and DNR efflux in peripheral blood lymphocytes were unchanged. These data indicated that P-gp activity was decreased in AA not only during the development of the disease, but also after remission, introducing a new concept on the pathophysiology of AA by suggesting that it may contribute to drug-induced injury to haemopoietic cells in some cases of AA, by increasing the proportion of susceptible cells.
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PMID:Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic anaemia: possible pathophysiologic implications. 975 37

Multidrug resistance (MDR), caused by overexpression of either P-glycoprotein or the multidrug resistance-associated protein (MRP), is characterized by a decreased cellular drug accumulation due to an enhanced drug efflux. Many studies on cells overexpressing MRP and/or Pgp, have shown a concentration of the drug inside cytoplasmic acidic vesicles followed by an exocytotic process. In this study, we examined the effects of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole or NBD (a H+-ATPase pump inhibitor), buthionine sulphoximine or BSO (an inhibitor of glutathione (GSH) biosynthesis) and verapamil or VPL (a calcium channel blocker) on the subcellular distribution of daunorubicin or DNR in K562 cells overexpressing MRP (K-H30) and Pgp (K-H300) and A549 cells overexpressing spontaneously MRP. Nucleo-cytoplasmic distribution of DNR was carried out using scanning confocal microspectrofluorometry. This technique allows determination of nuclear accumulation of anthracyclines. Our results show that nuclear accumulation of DNR in K-H30 and A549 cells was increased by NBD, BSO and VPL while in K-H300 cells, only VPL was able to increase nuclear accumulation of DNR. Similarly, NBD, BSO and VPL could reverse DNR resistance in K-H30 cells whereas, in K-H300 cells, only VPL increased the sensitivity of these cells. These data suggest a requirement for GSH in MRP-mediated resistance and suggest that even if vesicular sequestration can happen in cells overexpressing MRP and Pgp proteins, probably only the MRP protein is able to extrude the drug through intracellular vesicles and efflux. Finally, NBD and BSO might be a useful agents in facilitating discrimination between Pgp and MRP phenotypes and prognosis in patients.
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PMID:Characterization of H+-ATPase-dependent activity of multidrug resistance-associated protein in homoharringtonine-resistant human leukemic K562 cells. 976 97

Drug resistance remains a major problem in the treatment of patients with acute myeloid leukemia (AML). Expression of the MDR1 gene in leukemic cells was shown previously to be associated with worse clinical outcome of the patients. The multidrug resistance-associated protein (MRP) has been shown recently to be another protein causing the multidrug resistance phenotype in cell lines, but its impact on clinical outcome in patients with AML remains to be proven. To determine the clinical significance of MRP in patients with de novo AML, we have studied the MRP expression in leukemic cells and its association with both response to induction chemotherapy and survival of the patients. MRP gene expression was determined by immuno-cytochemistry (n = 80) by means of the monoclonal antibodies QCRL-1 and QCRL-3. MRP expression was low, intermediate, and high in 19, 55, and 26% of the patients, respectively. High MRP expression was independent of age and sex of the patients, WBC count, and percentage of blasts. However, high MRP expression was more frequent in the FAB M5 subtype as compared to the other subtypes. MRP expression had no impact on clinical outcome. The complete remission rates were 65, 68, and 63% for patients with low, intermediate, and high expression, respectively. Overall survival was also independent of MRP expression. In contrast, patients with P-glycoprotein-positive AML had lower complete remission rates and shorter durations of survival. These data indicate that MRP is expressed in patients with de novo AML but, in contrast to P-glycoprotein, does not predict for outcome of induction chemotherapy or survival.
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PMID:Multidrug resistance-associated protein in acute myeloid leukemia: No impact on treatment outcome. 981 27

Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated. To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50 micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.
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PMID:Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP). 981 3

To investigate the possible involvement of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and/or other glutathione S-conjugate export pump (GS-X pump) family members on the active efflux of irinotecan [(7-ethyl-10-[4-(1-piperidino)-1-pipertidino)-1-piperidino]carb onylox y camptothecin (CPT-11)] and its metabolites, as well as their contribution to the acquisition of resistance, we studied the uptake of CPT-11, its active metabolite SN-38, and glucuronide conjugate (SN38-Glu) using membrane vesicles from human epidermoid KB-3-1-derived cell lines. These lines included KB-C2, C-A500, and KCP-4, which overexpress P-gp, MRP, and the unidentified GS-X pump, respectively. The carboxylate form of SN-38 exhibited significant ATP-dependent transport, with a Michaelis constant of 17 microM, into membrane vesicles from C-A500 but not from other cell lines. Among these KB-derived cells, significant ATP-dependent uptake of the carboxylate form of CPT-11 was only observed in KB-C2 vesicles. In addition, the uptake of the lactone and carboxylate forms of SN38-Glu into membrane vesicles from C-A500 and KB-C2, but not KCP-4, was ATP dependent, although the transport activity in C-A500 was much higher than that in KB-C2. The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed that the resistance of KB-C2 to CPT-11 and SN-38, compared with that of KB-3-1, was 6.3- and 6.8-fold, respectively; the corresponding figures for C-A500 were 12- and 27-fold, respectively, whereas those for KCP-4 were 2.3- and 20-fold, respectively. These results suggest that MRP and P-gp are involved in the active efflux of SN-38 and CPT-11, respectively, from human KB-derived cells. In addition, a difference in substrate specificity among GS-X pump members was demonstrated.
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PMID:Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. 991 83

Acute myelogenous leukemia (AML) represents 80% of adult acute leukemias. A standard-dose chemotherapy allows to obtain 52% to 72% of complete remission (CR). A major limitation for success in chemotherapy of AML is dominance of drug-resistant subpopulations of cells. Cytosine-arabinoside (Ara-C) is a basic drug in AML treatment. Myeloblasts resistance to Ara-C could be kinetic or pharmacological. The classical multidrug resistance (MDR) depends on presence in resistant myeloblasts ATP-dependent drug-efflux pump with ability to remove cytotoxic drugs from the cells. It is a product of MDR1 gene called P-glycoprotein (Pgp). Pgp is responsible for cell resistance to cytotoxic compounds of natural origin, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, colchicine and amsacrine. There were also identified not Pgp-dependent multidrug resistance mechanisms (non-Pgp MDR) in AML. All mentioned above drugs are involved but not taxol. Non-Pgp MDR depends on topoisomerase II alfa activity alterations, multidrug resistance-associated protein (MRP) expression and lung resistance-related protein (LRP) expression. Pgp positive AML patients have poorer complete remission (CR) rate, decreased remission duration and overall survival. Pgp expression is detected among 70% AML patients older than 55. The most promising drugs in circumventing classical MDR seems cyclosporin A (CsA) and cyclosporin D (SDZ PCS 833). They are successfully used in refractory and relapsed AML.
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PMID:[The causes of treatment ineffectiveness in acute myelogenous leukemia--the role of blast resistance to cytotoxic drugs]. 1002 86

Expression of three major classes of glutathione S-transferases (GSTs), i.e. alpha, mu and pi class, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) were studied in childhood acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and normal peripheral blood lymphocytes by flow cytometry. In vitro cytotoxicity of 4-hydroxy-ifosfamide (IFOS), daunorubicin (DNR) and prednisolone (PRED) was assessed by the MTT assay. Expression of alpha, mu and pi class GST did not significantly differ between leukaemic cells from 100 initial and 14 unrelated relapse ALL patients (GSTalpha P=026; GSTmu P=O009; GSTpi P=0.13). The expression of GSTalpha (1.4-fold, P=0.0004), GSTpi (13-fold, P = 0001) and to a lesser extent also GSTmu (1.1-fold, P=0.03) was higher in ALL compared with normal peripheral blood lymphocytes. Expression of GSTmu and GST7pi was significantly higher in 18 AML compared with 100 ALL patients at initial diagnosis (respectively 1.3-fold, P=0.0005 and 2-fold, P<0.0001). In contrast, GSTalpha was median 2-fold lower expressed in the AML samples (P< 0.0001). Expression levels of alpha, mu and pi class GSTs were not related to the degree of resistance to IFOS, DNR and PRED nor to immunophenotype, white blood cell count or age at presentation of childhood ALL. One exception was a remarkably low expression of GSTalpha in IFOS-sensitive samples compared with a heterogenous expression in IFOS-resistant samples (P= 0.02). Expression of GSTpi, but not of GSTalpha or GSTmu, weakly correlated with the expression of MRP (Rs 0.36, P = 0.002, n = 74) but not with P-gp. However, a high expression of both GSTpi and MRP was not associated with in vitro resistance to IFOS, DNR or PRED. The present data suggest that expression of GSTs is not linked to the degree of resistance to IFOS, DNR and PRED or clinical risk factors in childhood ALL. Whether the high expression of GSTmu and GSTpi in AML cells contributes to the relative resistance to IFOS, DNR and PRED compared with ALL samples (P < or = 0.0001) warrants further study.
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PMID:Different expression of glutathione S-transferase alpha, mu and pi in childhood acute lymphoblastic and myeloid leukaemia. 1005 Jul 15

Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.
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PMID:Visualization of multidrug resistance in vivo. 1007 21


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