Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia

2008 ◽  
Vol 74B (3) ◽  
pp. 163-168 ◽  
Author(s):  
Lorena L. de Figueiredo-Pontes ◽  
Maria-Carolina T. Pintão ◽  
Luciana C. O. Oliveira ◽  
Leandro F. F. Dalmazzo ◽  
Rafael H. Jácomo ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Leukemic Stem Cells ◽  
Lung Resistance Protein ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Resistance Protein ◽  
Lung Resistance Protein Expression

Cyclosporine A Modulates the Multidrug Resistance Proteins P-Glycoprotein, Multidrug Resistance Protein, Breast Cancer Resistance Protein and Lung Resistance Protein.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1180-1180
Author(s):  
Misbah Qadir ◽  
Kieran L. O’Loughlin ◽  
Nicole A. Williamson ◽  
Hans Minderman ◽  
Maria R. Baer
Keyword(s):  
Multidrug Resistance ◽  
Broad Spectrum ◽  
Drug Distribution ◽  
Cancer Resistance ◽  
Lung Resistance Protein ◽  
Psc 833 ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Resistance Protein ◽  
In Cells

Abstract Multidrug resistance (MDR) mediated by the ATP-binding cassette proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1), breast cancer resistance protein (BCRP) and the vault protein lung resistance protein (LRP) is implicated in treatment failure in acute myeloid leukemia (AML). Pgp, MRP-1 and BCRP mediate energy-dependent cellular drug efflux, while LRP blocks cytoplasmic-nuclear drug transport. MDR modulators are non-cytotoxic drugs that block the activity of MDR proteins. In clinical trials, the Pgp modulator cyclosporine A (CsA) improved treatment outcome in AML, while its non-immunosuppressive, non-nephrotoxic analogue PSC-833 has not, despite being a potent Pgp modulator in preclinical models. CsA is known to also modulate MRP-1, and we hypothesized that a broad spectrum of MDR modulation might contribute to its clinical efficacy. We studied the effects of CsA and PSC-833 on in vitro drug uptake, retention and cytotoxicity in drug-selected and transfected resistant cell lines overexpressing Pgp, MRP-1 or BCRP, and on nuclear-cytoplasmic drug distribution and cytotoxicity in cell lines overexpressing LRP. Cellular drug content was measured by flow cytometry, and nuclear-cytoplasmic drug distribution was assessed by confocal microscopy. CsA enhanced uptake and retention of the substrate drug mitoxantrone in cells overexpressing Pgp (HL60/VCR), MRP-1 (HL60/ADR) and BCRP (8226/MR20) and increased cytotoxicity 7-, 4- and 4-fold, respectively. Moreover, CsA increased the nuclear content of doxorubicin in 8226/MR20 cells, which co-express LRP with BCRP, and increased doxorubicin cytotoxicity 12-fold. The effect of CsA on nuclear drug content and cytotoxicity in 8226/MR20 cells occurred without an effect on cellular doxorubicin content, consistent with the fact that 8226/MR20 cells co-express wild type BCRP (BCRPR482), which does not efflux doxorubicin. Moreover the BCRP modulator fumitremorgin C had no effect on 8226/MR20 content, nuclear uptake nor cytotoxicity of doxorubicin. CsA also enhanced nuclear doxorubicin content in a second cell line with LRP-mediated resistance, HT1080/DR4. PSC-833 enhanced mitoxantrone retention and cytotoxicity in cells overexpressing Pgp, but, in contrast to CsA, had no effect on mitoxantrone uptake, retention nor cytotoxicity in cells expressing MRP-1 nor BCRP, and had no effect on doxorubicin nuclear content nor cytotoxicity in cells expressing LRP. Thus CsA is a broad-spectrum MDR modulator, with activity against Pgp, MRP-1, BCRP and LRP, while PSC-833 only modulates Pgp. The broad-spectrum activity of CsA may contribute to its clinical efficacy. These findings support identification and testing of other broad-spectrum MDR modulators.

Expression of Multidrug Resistance 1, Lung Resistance Protein and Breast Cancer Resistance Protein Genes in Chronic Lymphocytic and Chronic Myelogeneous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4367-4367
Author(s):  
A. Ugur Ural ◽  
Ozlem Darcansoy Iseri ◽  
Pelin Kaya Mutlu ◽  
Meltem Demirel Kars ◽  
Ferit Avcu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Multidrug Resistance ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Expression Levels ◽  
Lung Resistance Protein ◽  
Chronic Myelogeneous Leukemia ◽  
Lung Resistance ◽  
Resistance Protein

Abstract One of the major problems in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents, which is already present at diagnosis or after chemotherapy as a minimal residual disease. The resistance may be originated from genetic or epigenetic mutations during prior growth of the leukemic clone. In this study, the expressions of three multidrug resistance (MDR) genes were investigated. Expression levels of multidrug resistance resistance gene 1 (MDR1), breast cancer resistance protein (BCRP) gene, and lung resistance protein (LRP) gene expression levels were determined in peripheral blood samples from 16 cases of chronic lymphocytic leukemia (CLL) and from 23 cases of chronic myelogeneous leukemia (CML) using RT-PCR. The expression of each of these genes was then expressed as a ratio in relation to β2-microglobulin gene expression in densitometric measurements. MDR1, BCRP and LRP expression levels was detected in 56,3%, 18,8% and 50% of CLL patients, respectively, with no difference for stage or response to the treatment. Four out of 16 (25%) CLL patients expressed none of these genes. The other 25% CLL patients expressed all of these genes. MDR1, BCRP and LRP expression was detected in 47,8%, 39,1% and 30,4% of CML patients, respectively, with no difference for progression or response to imatinib mesylate. Eight out of 23 (34,8%) CML patients expressed none of these genes. Four out of 23 (17,4%) CML patients expressed all of these genes, and two out of whom rapidly progressed to acute leukemia and unresponsive to the treatment. In conclusion, MDR and LRP overexpression seems to be a frequent event in CLL and CML patients; however no conclusion can be drawn on their prognostic role and response to the treatment.

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