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)

P-glycoprotein (P-gp) is a 170 kDa transmembrane glycoprotein which plays a significant role in modulating pleomorphic or multiple drug resistance (MDR) in a wide variety of human cancers like renal and colorectal carcinoma. However, its role in modulating drug resistance in other types of cancer is less well defined. The purpose of this review is to critically examine the evidence that P-gp plays an important role in producing drug resistance in astrocytic gliomas. Malignant astrocytoma is clinically resistant to most types of cytotoxic drugs, including those associated with the MDR phenotype and the cross-resistance patterns of short-term cultures derived from malignant glioma are consistent with this phenotype. Consequently, it might be expected that this tumor would express high levels of P-gp. However, immunohistochemical findings from a number of previous studies have provided conflicting data about the expression of P-gp in these tumors, although P-gp has been consistently detected in normal brain in the endothelial cells in cerebral blood vessels and is thought to contribute to the blood-brain barrier phenomena. In order to determine if P-gp contributes to drug resistance in malignant astrocytoma, we undertook a study of P-gp expression in a panel of short-term cultures derived from these tumors in which we determined the in vitro chemosensitivity. However, immunocytochemical studies with a panel of antibodies which recognize both internal and external epitopes of the P-gp molecule have consistently failed to show the characteristic membrane staining associated with MDR in any of the cultures, including those markedly cross-resistant to vincristine and doxorubicin. One antibody, JSB-1, showed heterogeneous granular cytoplasmic staining which was unrelated to a particular pattern of drug resistance. This is probably because this antibody cross-reacts with a widely distributed cytoplasmic antigen, pyruvate carboxylase, which is present in abundance in normal astrocytes. The unexpectedly poor specificities of many of the antibodies thought to be specific for P-gp is reviewed in the context of malignant astrocytoma. In conclusion, the role of P-gp in producing drug resistance in malignant astrocytoma is questionable and further studies might more profitably concentrate on the mechanisms of resistance to DNA-damaging agents like the nitrosoureas, methylating agents or platinum-based drugs.
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PMID:Does P-glycoprotein play a role in clinical resistance of malignant astrocytoma? 1063 Mar 53

1. P-Glycoprotein is a 170-kDa transmembrane glycoprotein active efflux system that confers multidrug resistance in tumors, as well as normal tissues including brain. 2. The classical model of multidrug resistance in brain places the expression of P-glycoprotein at the luminal membrane of the brain microvascular endothelial cell. However, recent studies have been performed with human brain microvessels and double-labeling confocal microscopy using (a) the MRK16 antibody to human P-glycoprotein, (b) an antiserum to glial fibrillary acidic protein (GFAP), an astrocyte foot process marker, or (c) an antiserum to the GLUT1 glucose transporter, a brain endothelial plasma membrane marker. These results provide evidence for a revised model of P-glycoprotein function at the brain microvasculature. In human brain capillaries, there is colocalization of immunoreactive P-glycoprotein with astrocytic GFAP but not with endothelial GLUT1 glucose transporter. 3. In the revised model of multidrug resistance in brain, P-glycoprotein is hypothesized to function at the plasma membrane of astrocyte foot processes. These astrocyte foot processes invest the brain microvascular endothelium but are located behind the blood-brain barrier in vivo, which is formed by the brain capillary endothelial plasma membrane. 4. In the classical model, an inhibition of endothelial P-glycoprotein would result in both an increase in the blood-brain barrier permeability to a given drug substrate of P-glycoprotein and an increase in the brain volume of distribution (VD) of the drug. However, in the revised model of P-glycoprotein function in brain, which positions this protein transporter at the astrocyte foot process, an inhibition of P-glycoprotein would result in no increase in blood-brain barrier permeability, per se, but only an increase in the VD in brain of P-glycoprotein substrates.
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PMID:Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. 1069 8

P-glycoprotein (P-gp) is a transmembrane glycoprotein that confers multidrug resistance (MDR). It has been demonstrated that the Gly185 residue within the cytoplasmic loop between predicted transmembrane portions 2 and 3 plays an important role in substrate specificity of human P-gp. Derivatives of cyclosporin interact with and reverse the ability of P-gp to act as a drug efflux pump. To determine if the Gly185 residue of human P-gp is also important for the interaction of P-gp with closely related cyclosporin derivatives, we examined the effect of PSC-833 and CsA on P-gp in KB3-1 cells transfected with human wild-type P-gp (GSV-2) or with the mutant P-gp (VSV-1) that habored the Gly185-->Val substitution. While the ability of CsA to sensitize VSV-1 cells to anticancer agents was enhanced, no changes in the potency of PSC-833 against cells transfected with either the wild-type or mutant P-gp were observed. In addition, VSV-1 transfected cells were more sensitive to CsA inhibition of verapamil-stimulated ATPase activity than cells transfected with wild-type P-gp. Furthermore, the intracellular accumulation of CsA was low in GSV-2 P-gp-expressing cells, compared with its accumulation in VSV-1 cells and it was found to be as high as in non-P-gp expressing KB3-1 cells. These results indicated an enhanced sensitivity of Val185-P-gp expressing cells to CsA that correlated with increased intracellular accumulation in these cells. In contrast, no significant difference in the accumulation of PSC-833 was observed among the parental, wild-type or resistant cells. Since PSC-833 was found to be more potent than CsA, these studies provided insight into the effects of the structure of MDR modulators in mediating sensitivity to anticancer drugs.
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PMID:Altered activity of MDR-reversing agents on KB3-1 cells transfected with Gly(185)-->Val human P-glycoprotein. 1093 1

Multidrug-resistance 1 (MDR1) encodes a 170 kDa transmembrane glycoprotein (P-glycoprotein), which acts as a drug-efflux pump. In the present study, we analyzed the expression of MDR1/P-glycoprotein in human pancreatic cancer and correlated the results with clinical parameters. Pancreatic cancer tissue samples were obtained from 67 patients (30 female, 37 male) who underwent surgery. Normal pancreatic tissues obtained from 15 previously healthy organ donors (4 female, 11 male) served as controls. MDR1 mRNA levels were analyzed by Northern blotting, and the exact site of MDR1 mRNA expression was determined by in situ hybridization and immunohistochemistry. Northern blot analysis indicated that in comparison with the normal pancreas, MDR1 mRNA levels were only increased 1.4-fold (p = 0.03) in the pancreatic cancer samples. However, there was a 2.9-fold (p < 0.01) increase in MDR1 mRNA levels when only the samples that exhibited increased expression (38%) were analyzed. In situ hybridization and immunohistochemical analysis showed that MDR1 was highly expressed in the cancer cells of these samples. Statistical analysis revealed that patients with high MDR1/P-glycoprotein expression had a shorter postoperative survival time compared with patients with weak to moderate expression of MDR1. On the basis of in situ hybridization, survival in the intense group was 11.6 (n = 12) versus 14.2 months (n = 42) in the mild to moderate group. On the basis of immunohistochemistry, survival in the intense group was 7.5 months (n = 10) versus 14.1 months (n = 40) in the mild to moderate group. Surprisingly, survival of patients with high expression of MDR1/P-glycoprotein was not significantly different from that of patients without detectable MDR1/P-glycoprotein expression. These findings suggest that both strong expression of MDR1/P-glycoprotein and lack of expression seem to influence tumor growth via known and yet unknown mechanisms.
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PMID:Expression of the multidrug-resistance 1 (MDR1) gene and prognosis in human pancreatic cancer. 1103 67

One of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR). The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the MDR1 gene, which encodes a transmembrane glycoprotein named P-glycoprotein (P-gp). This study evaluated whether bromocriptine, a D2 dopaminergic receptor agonist, influenced anticancer drug cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. The K(i) values for P-gp of cyclosporine and verapamil were 1.09 and 540 microM, respectively, and that of bromocriptine was 6.52 microM in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 microM reduced the IC50 of doxorubicin (DXR) in K562-DXR from 9000 to 270 ng/ml and that of vincristine (VCR) in K562-VCR from 700 to 0.30 ng/ml, whereas the IC50 values of DXR and VCR in the K562 subline were only marginally affected by these drugs. Bromocriptine restored the anticancer effect of DXR, VCR, vinblastine, vinorelbine and etoposide on MDR-tumor cells overexpressing P-gp. These observations suggest that bromocriptine has the potential to reverse tumor MDR involving the efflux protein P-gp in the clinical situation.
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PMID:Bromocriptine reverses P-glycoprotein-mediated multidrug resistance in tumor cells. 1185 85

The RNA-guided clustered regularly interspaced short palindromic (CRISPR) in combination with a CRISPR-associated nuclease 9 (Cas9) nuclease system is a new rapid and precise technology for genome editing. In the present study, we applied the CRISPR/Cas9 system to target ABCB1 (also named MDR1) gene which encodes a 170 kDa transmembrane glycoprotein (P-glycoprotein/P-gp) transporting multiple types of chemotherapeutic drugs including taxanes, epipodophyllotoxins, vinca alkaloids and anthracyclines out of cells to contribute multidrug resistance (MDR) in cancer cells. Our data showed that knockout of ABCB1 by CRISPR/Cas9 system was succesfully archieved with two target sgRNAs in two MDR cancer cells due to the alteration of genome sequences. Knockout of ABCB1 by CRISPR/Cas9 system significantly enhances the sensitivity of ABCB1 substrate chemotherapeutic agents and the intracellular accumulation of rhodamine 123 and doxorubicin in MDR cancer cells. Although now there are lots of limitations to the application of CRISPR/Cas9 for editing cancer genes in human patients, our study provides valuable clues for the use of the CRISPR/Cas9 technology in the investigation and conquest of cancer MDR.
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PMID:Targeting ABCB1-mediated tumor multidrug resistance by CRISPR/Cas9-based genome editing. 2772 79


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