Expression of MDR1/P-Glycoprotein, the Multidrug Resistance Protein MRP, and the Lung-Resistance Protein LRP in Multiple Myeloma

2002 ◽  
Vol 19 (2) ◽  
pp. 87-104 ◽  
Author(s):  
Heidi Schwarzenbach
Keyword(s):  
Multiple Myeloma ◽  
Multidrug Resistance ◽  
Multidrug Resistance Protein ◽  
Lung Resistance Protein ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Resistance Protein

scholarly journals Relationship Between Major Vault Protein/Lung Resistance Protein, Multidrug Resistance-Associated Protein, P-Glycoprotein Expression, and Drug Resistance in Childhood Leukemia

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 2092-2098 ◽  
Author(s):  
M.L. den Boer ◽  
R. Pieters ◽  
K.M. Kazemier ◽  
M.M.A. Rottier ◽  
C.M. Zwaan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Major Vault Protein ◽  
Lung Resistance Protein ◽  
P Glycoprotein ◽  
Lung Resistance ◽  
Resistance Protein

Cellular drug resistance is related to a poor prognosis in childhood leukemia, but little is known about the underlying mechanisms. We studied the expression of P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein (MRP), and major vault protein/lung resistance protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL) and 27 with acute myeloid leukemia (AML) by flow cytometry. The expression was compared between different types of leukemia and was studied in relation with clinical risk indicators and in vitro cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine (VCR), and etoposide (VP16) and the non–MDR-related drugs prednisolone (PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression did not differ between 112 initial and 29 unrelated relapse samples nor between paired initial and relapse samples from 9 patients. In multiple relapse samples, LRP expression was 1.6-fold higher compared with both initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was weakly but significantly related to in vitro resistance to DNR (Spearman's rank correlation coefficient 0.25, P = .016) but not to VCR, VP16, PRD, and ASP. No significant correlations were found between P-gp or MRP expression and in vitro drug resistance. Samples with a marked expression of two or three resistance proteins did not show increased resistance to the tested drugs compared with the remaining samples. The expression of P-gp, MRP, and LRP was not higher in initial ALL patients with prognostically unfavorable immunophenotype, white blood cell count, or age. The expression of P-gp and MRP in 20 initial AML samples did not differ or was even lower compared with 112 initial ALL samples. However, LRP expression was twofold higher in the AML samples (P < .001), which are more resistant to a variety of drugs compared with ALL samples. In conclusion, P-gp and MRP are unlikely to be involved in drug resistance in childhood leukemia. LRP might contribute to drug resistance but only in specific subsets of children with leukemia.

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.

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