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)

Acquired resistance to chemotherapeutic drugs by tumor cells is an important obstacle to effective therapy of human malignancy. These resistance cell lines originated from human or rodent have been characterized by increased expression of MDR (Multidrug-resistance) gene and P-glycoprotein which plays as efflux pump of drugs from cells. These multidrug-resistance sublines also have been reported increased activities of protein kinases and glutathione S-transferase-pi. Although there have been extensive biophysical and biochemical characterization of the differences between parental lines and MDR tumor cell sublines, morphologic observations have been limited. In this study, filamentous cytoskeletons which involve many biological phenomena such as maintenance of cell morphology, mitosis, cellular movement, transport, and adhesion, were observed by confocal laser microscopy. To compare the expression of each cytoskeletons, fluorescent intensities of cells stained for each cytoskeletons were measured by confocal laser microscopic system. Utilizing this methodology, higher microtubular expression was observed in HL-60/ADR and K562/ADR than in their parental lines, but no significant differences of actin and vimentin were observed. Phosphorylation by protein kinases has been established as a key factor in the regulation of cytoskeletal function. But little is known about the role of protein phosphorylation in cytoskeletal function. Since increased activities of PKC and PTK were detected in HL-60/ADR, the effect of PKC inhibitor, staurosporine (STR), or PTK inhibitor, genistein (GNS), on cell growth was detected. STR and GNS reduced the resistance to Adriamycin in HL-60/ADR. Furthermore, STR and GNS disrupted the filamentous structure of microtubules in HL-60/ADR, and suppressed the expression of microtubules to 37%, and 49%, respectively. In contrast, PKC activator, phorbol ester (TPA), caused stronger microtubular assembling in HL-60/ADR, and increased the expression of microtubules to 134%. Resulting from this study, it is likely that acquired MDR of HL-60 and K562 was associated with increased expression of microtubules, and microtubular assembling or disassembling was considered to be regulated in part by PKC and PTK.
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PMID:[Features of filamentous cytoskeletons in acquired multidrug-resistance of HL-60 human leukemia cell line]. 790 88

A cell line, GBM, was established from a human malignant glioblastoma and was characterized with particular reference to its response to conventional drugs. The GBM cell line exhibited a 73 +/- 7 h doubling time in monolayer cultures. Expression of glial fibrillary acidic and S-100 proteins was observed. Karyotype analysis of GBM cells at early passages revealed the presence of two near-triploid clones (A and B) with multiple chromosome rearrangements; a 100% frequency for clone B was observed in the established cell line. GBM cells had tumorigenic properties, since the s.c. injection of cultured cells into nude mice gave rise to slowly growing tumors. The morphology of GBM cells was retained during in vitro and in vivo passages, as judged by light microscopy. GBM cells were relatively resistant to most conventional drugs; among the tested drugs, only taxol exhibited a marked cytotoxic effect comparable to that found in cells of a different tumor type. GBM cells were found positive for the epidermal growth factor receptor, HER2-neu and P-glycoprotein by flow cytometry of cells labelled with monoclonal antibodies. In spite of the expression of relatively high gamma-glutamyltransferase activity, the intracellular glutathione level was comparable to that of other chemosensitive tumor cells. This glioblastoma cell line is a suitable model for the identification and preclinical studies of new agents and provides an additional system to explore the molecular basis of the intrinsic drug resistance of glioblastoma.
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PMID:Characterization of an established human, malignant, glioblastoma cell line (GBM) and its response to conventional drugs. 792 29

Natural killer (NK) cells have been reported recently to be the highest in expressing multidrug resistance (MDR) P-glycoprotein among normal mature lymphoid cells. Using a cultured NK cell-rich population, we have examined the expression and function of P-glycoprotein, in particular its role in NK cell-mediated cytotoxicity, by employing two MDR-reversing agents (nicardipine and AHC-52, a nicardipine analog almost devoid of calcium channel blocking activity) and monoclonal antibody against P-glycoprotein (MRK-16). The expression of P-glycoprotein was detected by flow cytometry and polymerase chain reaction of reverse transcribed mRNA. P-glycoprotein was functional in terms of rhodamine dye excretion and its susceptibility to the MDR-reversing agents. Since the concentration of nicardipine required for 50% inhibition (IC50) of rhodamine dye excretion (2 microM) was close to that of AHC-52 (5 microM), it was suggested that their inhibitory effects were not due to calcium channel blocking activity, and that ACH-52 is a selective inhibitor for P-glycoprotein. The IC50 of nicardipine for NK cell-mediated cytotoxicity (33 microM) was also close to that of AHC-52 (26 microM), indicating that P-glycoprotein is involved in NK cell-mediated cytotoxicity. In support of this, MRK16 inhibited NK cell-mediated cytotoxicity in a concentration-dependent manner. Both binding of target cells to NK cells and post-binding events were affected by AHC-52, suggesting that P-glycoprotein is involved in several steps in NK cell-mediated cytotoxicity.
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PMID:Expression and function of multidrug resistance P-glycoprotein in a cultured natural killer cell-rich population revealed by MRK16 monoclonal antibody and AHC-52. 798 Jun 29

Relationships between the incidence of metastatic spread and microvessel density, expression of proto-oncogene products, or expression of resistance-related proteins were investigated in human ovarian carcinomas by immunohistochemistry. Ovarian carcinomas with a high microvessel density showed a significantly increased formation of metastases (P = 0.005). Tumors with positive immunoreactivity of c-jun and c-myc products had a higher metastatic spread; however, these results were not statistically significant. A marginally significant correlation existed between the expression of erbB1 (EGFR) and metastatic spread (P = 0.05). No significant relationship was found between the expression of the resistance-related proteins P-glycoprotein or glutathione S-transferase-pi and the incidence of metastases. Furthermore, no correlation was detected between expression of the heat shock protein 70 and the occurrence of metastases.
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PMID:Microvessel density, expression of proto-oncogenes, resistance-related proteins and incidence of metastases in primary ovarian carcinomas. 867 74

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo acute myeloid leukemia (AML) at the initial diagnosis in order to further define the relationship between the presence of P-gp on leukemic cells and the efficacy of two different anthracycline drugs, Daunorubicin (DNR) and Idarubicin (IRR), in terms of remission, induction and survival. We found that 30 (60%) of the 50 patients were negative for P-gp expression (group 1) and 20 patients (40%) were positive (group 2) for P-gp expression by MRK16MoAb using a cut of 10% positive cells. Among the 50 patients, 35 (70%) obtained complete remission (CR); depending on P-gp expression the CR rate was 80% for group 1 and 45% for group 2 (p < 0.005). The median duration of overall survival (OS) was 20 months for patients in group 1, compared to 10 months for patients in group 2 (p < 0.005). Regarding the anthracycline used, no difference in CR has been observed in patients of group 1 (75% CTR with DNR versus 90% CR with IDR); on the contrary in group 2 we observed 40% CR with DNR versus 70% CR with IDR (p < 0.005). No significant difference has been achieved in group 1 terms of median duration of overall survival between DNR and IDR regimen; on the contrary the median duration of OS in patients of group 2 treated with IDR regimen was significantly longer than DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at diagnosis and we suggest that Idarubicin could be a valid anthracycline drug for reversing multidrug resistance.
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PMID:Anthracycline drugs and MDR expression in human leukemia. 886 11

In the central nervous system the blood-brain and blood-retinal barriers (BBB and BRB respectively) are instrumental in maintaining homeostasis of the neural parenchyma and controlling leucocyte traffic. These cellular barriers are formed primarily by the vascular endothelium of the brain and retina although in the latter the pigmented epithelial cells also form part of the barrier. From primary cultures of rat brain endothelium, retinal endothelium and retinal pigment epithelium (RPE) we have generated temperature sensitive SV40 large T immortalised cell lines. Clones of brain (GP8.3) and retinal (JG2.1) endothelia and RPE (LD7.4) have been derived from parent lines that express the large T antigen at the permissive temperature. The endothelial cell (EC) lines expressed P-glycoprotein, GLUT-1, the transferrin receptor, von Willebrand factor and the RECA-1 antigen and exhibited high affinity uptake of acetylated LDL and stained positive with the lectin Griffonia simplicifolia. The RPE cell line was positive for cytokeratins and for the rat RPE antigen RET-PE2. All the cell lines expressed major histocompatibility complex (MHC) class 1 and intercellular adhesion molecule (ICAM)-1 constitutively and could be induced to express MHC class II and vascular cell adhesion molecule (VCAM)-1 following cytokine activation. The EC also expressed platelet endothelial cell adhesion molecule (PECAM)-1. Monolayers of these cells could support the migration of antigen-specific T cell lines. The generation of immortalised cell lines derived from the rat BBB and BRB should prove to be useful tools for the study of these specialised cellular barriers.
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PMID:SV40 large T immortalised cell lines of the rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. 898 3

We previously showed that combined neoadjuvant doxorubicin (DOX) treatment and orthotopic liver transplantation produced a 3-year tumor-free survival rate of 54% in stage II-IVa nonresectable hepatocellular carcinomas (HCCs). These patients received posttransplant immunosuppressive doses of cyclosporin A (CsA). CsA has been shown to modify the function of a membrane P-glycoprotein (Pgp) whose overexpression is associated with a multidrug-resistant (MDR1) phenotype. This study utilized HCC cell lines to characterize the in vitro chemomodulatory properties of CsA as found in posttransplant patient plasma to consider the hypothesis that CsA may prolong posttransplant survival by enhancing the therapeutic efficacy of DOX against multidrug-resistant hepatoma cells. We characterized Pgp expression in the HCC lines Hep3B, Hep G2, and SK-HEP-1 by immunohistochemistry and the reverse transcription-polymerase chain reaction. The combined cytotoxicity of DOX + CsA was examined by [3H]thymidine uptake and flow cytometric drug-retention assays. Pgp expression was assessed further after prolonged (10-day) treatment with CsA. Hep3B and Hep G2 cells expressed low to moderate levels of Pgp. The effective DOX dose required for inhibiting MDR1(+) Hep3B and Hep G2 cell proliferation by 50% (DOX IC50) was 44.5 ng/ml and 43.5 microgram/ml, as compared with 10.7 ng/ml for Pgp-negative SK-HEP-1 cells. Optimal concentrations of CsA (0.8 micrometer) lowered DOX IC50 for Hep3B cells and Hep G2 cells by 6-fold and 4-fold, respectively. Similarly, plasma from patients containing immunosuppressive levels of CsA lowered DOX IC50 of the MDR1(+) Hep G2 cells by up to 4-fold. Prolonged exposure to CsA did not affect its chemosensitizing capacity or Pgp expression of HCC cells. PSC-833, a nonimmunosuppressive analogue of CsA, was equally effective in reducing the DOX IC50 of MDR1(+) HCC cells. CsA and PSC-833 increased drug retention by approximately 75%, but did not significantly affect hepatoma cell viability or Pgp expression. Pharmacological concentrations of cyclosporin analogues, including one nonimmunosuppressive form, enhance DOX cytotoxicity of MDR1(+) HCC cells by modulating drug retention. CsA as found in posttransplant patient plasma enhanced DOX cytotoxicity to human MDR1(+) hepatoma cells in vitro, albeit at less than optimal chemosensitizing concentrations. Prolonged exposure to CsA did not affect its chemosensitizing properties or block Pgp expression of HCC cells. These findings support our hypothesis that in vivo immunosuppressive levels of CsA may enhance DOX chemotherapeutic efficacy on MDR1(+) HCC cells.
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PMID:Chemosensitization of human hepatocellular carcinoma cells with cyclosporin A in post-liver transplant patient plasma. 981

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

The MDR1 gene encoding the multidrug pump P-glycoprotein is transcriptionally activated in response to diverse extracellular stimuli, including the tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the signal transduction pathway responsible is unknown. Downstream of protein kinase C (PKC), the effects of TPA are often mediated by the Raf-1/MEK/ERK mitogen-activated protein kinase (MAPK) cascade, and Raf-1 has been implicated in MDR1 induction by serum and mitogens. Therefore, we examined the potential role of MAPK activation in TPA-mediated MDR1 induction in human leukemia K562 cells. MDR1 mRNA expression was significantly increased by TPA in the concentration range of 4 - 100 nM, with a maximal response 5 - 10 h after TPA addition. TPA-mediated MDR1 induction was inhibited by several PKC inhibitors including staurosporine, H7 and calphostin C. TPA stimulated the subcellular translocation of PKCalpha from the cytosol to the membrane and nucleus but did not affect other PKC isozymes. TPA also activated the Raf1/MEK/ERK cascade and activated another MAPK member, p38, but not JNK. In order to determine the potential role of MAPKs in MDR1 induction by TPA, specific inhibitors were utilized. The MEK inhibitor PD 098059, as well as the PKC inhibitors, completely blocked TPA-mediated ERK activation. However, under identical conditions, MDR1 induction by TPA was completely unaffected by PD 098059. Furthermore, SB 202190, which effectively inhibited TPA-mediated p38 activation, failed to inhibit TPA-induced MDR1 mRNA expression. These data demonstrate that MDR1 induction by TPA occurs via a PKC-dependent mechanism that operates independently of ERK, p38 or JNK pathways, and thus have important implications for understanding the mechanisms of MDR1 induction by extracellular stimuli.
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PMID:Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. 1052 56

Active efflux from procaryotic as well as eucaryotic cells strongly modulates the activity of a large number of antibiotics. Effective antibiotic transport has now been observed for many classes of drug efflux pumps. Thus, within the group of primary active transporters, predominant in eucaryotes, six families belonging to the ATP-binding cassette superfamily, and including the P-glycoprotein in the MDR (Multi Drug Resistance) group and the MRP (Multidrug Resistance Protein), have been recognized as being responsible for antibiotic efflux. Within the class of secondary active transporters (antiports, symports, and uniports), ten families of antibiotic efflux pumps have been described, distributed in five superfamilies [SMR (Small Multidrug Resistance), MET (Multidrug Endosomal Transporter), MAR (Multi Antimicrobial Resistance), RND (Resistance Nodulation Division), and MFS (Major Facilitator Superfamily)]. Nowadays antibiotic efflux pumps are believed to contribute significantly to acquired bacterial resistance because of the very broad variety of substrates they recognize, their expression in important pathogens, and their cooperation with other mechanisms of resistance. Their presence also explains high-level intrinsic resistances found in specific organisms. Stable mutations in regulatory genes can produce phenotypes of irreversible multidrug resistance. In eucaryotes, antibiotic efflux pumps modulate the accumulation of antimicrobials in phagocytic cells and play major roles in their transepithelial transport. The existence of antibiotic efflux pumps, and their impact on therapy, must now be taken fully into account for the selection of novel antimicrobials. The design of specific, potent inhibitors appears to be an important goal for the improved control of infectious diseases in the near future.
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PMID:Antibiotic efflux pumps. 1087 20


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