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)

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1-encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.
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PMID:Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. 197 61

A subset of patients with chronic lymphocytic leukemia (CLL) and nearly all patients with classic hairy cell leukemia (HCL) harbor somatic BRAF activating mutations. However, the pathological role of activated BRAF in B-cell leukemia development and progression remains unclear. In addition, although HCL patients respond well to the BRAFV600E inhibitor vemurafenib, relapses are being observed, suggesting the development of drug resistance in patients with this mutation. To investigate the biological role of BRAFV600E in B-cell leukemia, we generated a CLL-like B-cell line, OSUCLL, with doxycycline-inducible BRAFV600E expression. Microarray and real-time PCR analysis showed that ABCB1 mRNA is upregulated in these cells, and P-glycoprotein (P-gp) expression as well as function were confirmed by immunoblot and rhodamine exclusion assays. Additionally, pharmacological inhibition of BRAFV600E and MEK alleviated the BRAFV600E-induced ABCB1/P-gp expression. ABCB1 reporter assays and gel shift assays demonstrated that AP-1 activity is crucial in this mechanism. This study, uncovers a pathological role for BRAFV600E in B-cell leukemia, and provides further evidence that combination strategies with inhibitors of BRAFV600E and MEK can be used to delay disease progression and occurrence of resistance.
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PMID:BRAFV600E induces ABCB1/P-glycoprotein expression and drug resistance in B-cells via AP-1 activation. 2635 Jan 41

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