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)

The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell- and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340, through monolayers of Caco-2 cells in vitro.
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PMID:Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. 2285 May 10

Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.
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PMID:Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2. 2308 5

Multidrug resistance (MDR) is a major obstacle in the treatment of cancer. Overexpression of P-glycoprotein (P-gp), encoded by the ABCB1 (MDR1) gene, is an important factor in determining the MDR phenotype of a tumour. Although recent studies have revealed the epigenetic transcriptional regulation of the human ABCB1 gene, such regulation of this gene has not been examined in dogs. The aim of the current study was to evaluate differences in epigenetic regulation of the ABCB1 gene, between drug-sensitive and drug-resistant canine lymphoid tumour cell lines. In two drug-sensitive cell lines, GL-1 and CLBL-1, ABCB1 mRNA expression was significantly lower than in two drug-resistant cell lines, UL-1 and Ema, using real-time quantitative polymerase chain reaction (QPCR). Bisulphite sequencing and real-time methylation-specific PCR revealed that the CpG island present in the upstream region of exon 2 was hypermethylated in GL-1 and CLBL-1, but hypomethylated in UL-1 and Ema. Chromatin immunoprecipitation and QPCR revealed that histone H3 acetylation in the same CpG island was significantly increased in UL-1 and Ema compared to GL-1 and CLBL-1. Treatment with 5-aza 2'-deoxycytidine or trichostatin A increased ABCB1 mRNA expression in GL-1 and CLBL-1. DNA methylation and histone H3 acetylation were shown to be involved in ABCB1 gene expression and associated with an MDR phenotype in these canine lymphoid tumour cell lines.
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PMID:Epigenetic regulation of the ABCB1 gene in drug-sensitive and drug-resistant lymphoid tumour cell lines obtained from canine patients. 2433 6

Acquisition of multidrug resistance (MDR) is a common cause of treatment failure during chemotherapy for dogs with lymphoma (lymphosarcoma). Overexpression of P-glycoprotein (P-gp), encoded by the ABCB1 gene, is associated with MDR. Perifosine, an Akt inhibitor, downregulates the expression of P-gp. In this study, the antitumour effect of perifosine and its ability to modulate ABCB1 expression were examined in four canine lymphoid tumour cell lines (GL-1, CLBL-1, UL-1 and Ema). GL-1 and CLBL-1 were inherently negative for P-gp, while UL-1 and Ema were inherently positive for P-gp. GL-1 and UL-1 were sensitive to perifosine, whereas CLBL-1 and Ema were resistant. The amount of ABCB1 mRNA significantly decreased after treatment with perifosine in UL-1, associated with activation of the c-Jun NH2-terminal kinase (JNK) pathway, but such an effect was not observed in Ema. In UL-1, perifosine decreased the efflux of rhodamine 123 dye and reduced the 50% inhibitory concentration of vincristine, but such effects were not observed in Ema. Perifosine had an antitumour effect in 2/4 canine lymphoid tumour cell lines. In 1/4 cell lines, perifosine downregulated ABCB1 gene expression through activation of the JNK pathway and increased sensitivity to vincristine.
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PMID:Antitumour effect and modulation of expression of the ABCB1 gene by perifosine in canine lymphoid tumour cell lines. 2488 8

Canine lymphoma is routinely treated with a doxorubicin-based multidrug chemotherapy protocol, and although treatment is initially successful, tumor recurrence is common and associated with therapy resistance. Active efflux of chemotherapeutic agents by transporter proteins of the ATP-Binding Cassette superfamily forms an effective cellular defense mechanism and a high expression of these transporters is frequently observed in chemotherapy-resistant tumors in both humans and dogs. In this study we describe the ABC-transporter expression in a canine lymphoid cell line and a sub-cell line with acquired drug resistance following prolonged exposure to doxorubicin. This sub-cell line was more resistant to doxorubicin and vincristine, but not to prednisolone, and had a highly increased P-glycoprotein (P-gp/abcb1) expression and transport capacity for the P-gp model-substrate rhodamine123. Both resistance to doxorubicin and vincristine, and rhodamine123 transport capacity were fully reversed by the P-gp inhibitor PSC833. No changes were observed in the expression and function of the ABC-transporters MRP-1 and BCRP. It is concluded that GL-40 cells represent a useful model for studying P-gp dependent drug resistance in canine lymphoid neoplasia, and that this model can be used for screening substances as potential P-gp substrates and their capacity to modulate P-gp mediated drug resistance.
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PMID:Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma. 2497 8

Lymphoma is the most common hematopoietic tumor in dogs and humans, with similar pathogenesis and therapeutic responses. Anticancer drugs like vincristine (VCR) and doxorubicin (DOX) are often used in treating lymphoma. However, the cure rate is generally poor due to chemoresistance. Here, we sought to determine whether stearidonic acid (SDA), a plant-based dietary fatty acid, sensitizes chemoresistant canine lymphoid-tumor cells. GL-1 B-cell lymphoid-tumor cells were found to be highly sensitive to the antitumor-activity of VCR and DOX, while OSW T-cell and 17-71 B-cell lymphoid-tumor cells were moderately and fully resistant, respectively. SDA, at its non-toxic concentrations, significantly promoted the antitumor action of VCR and DOX in both OSW and 17-71 cells. SDA-mediated chemosensitization was associated with SDA inhibition of P-glycoprotein (P-gp) function. This was confirmed in HEK293 cells stably expressing P-gp as well as by increased binding-affinity of SDA to P-gp in P-gp docking analysis. SDA at its chemosensitizing concentrations did not affect the viability of healthy dog peripheral blood mononuclear cells, suggesting that SDA is non-toxic to normal dog peripheral blood leucocytes at its chemosensitizing concentrations. Our study identifies a novel dietary fatty acid that may be used as a dietary supplement in combination with chemotherapy to promote the antitumor efficacy of the chemotherapy drugs in dogs and possibly in humans with chemoresistant lymphoma.
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PMID:Stearidonic acid, a plant-based dietary fatty acid, enhances the chemosensitivity of canine lymphoid tumor cells. 2584 97

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.
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PMID:Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. 2692 60

Drug resistance has been shown to be associated with the expression of P-glycoprotein (P-gp), the product of the mdr-1 gene. In the present study the expression of P-gp in 57 cases B-cell non Hodgkin lymphoma NHL was assessed before chemotherapy. Six cases of reactive lymphoid tissue and 11 cases of solid tumors were also studied. The expression of P-gp was evaluated by immunocyto- and histochemical methods, using three different Monoclonal Antibodies C219, JSB-1 and MRK16 directed against separate epitopes of P-gp. Comparable frequencies of cases positive for P-gp were found in low grade (6/40) and high grade (3/17) lymphomas. The pattern of staining was predominantly cytoplasmic, although a Golgi-associated dot like pattern of staining was also seen, mostly with JSB-1 MAb. Both cases of Hairy cell leukemia were P-gp positive. P-gp expression was also found in the endothelium of small capillaries and some high endothelial venules, as well as in macrophages, in both lymphomas and reactive lymphoid tissues. P-gp expression was found in a low frequency in NHL, suggesting that clinical drug resistance may already be predicted at the time of diagnosis and thus may serve as a guide in the choice of chemotherapeutical regiment.
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PMID:Expression of P-Glycoprotein in Non-Hodgkin's Lymphomas. 2746 49

T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2',7'-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs.
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PMID:Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies. 3307 33


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