ABSTRACT
The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding-cassette transporter involved in the transport of drugs used in the treatment of multiple myeloma (MM). Its expression, function and clinical significance in MM, however, are unknown. We report that BCRP is preferentially expressed and functionally active in normal plasma cells but that its function is significantly impaired in plasma cells in newly diagnosed MM. The data presented argue against a role for BCRP in primary drug resistance in MM and the utilisation as a molecular target as such but warrant research into its (patho)physiological role in normal and malignant plasma cells.
Subject(s)
ATP-Binding Cassette Transporters/physiology , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Multiple Myeloma/pathology , Neoplasm Proteins/physiology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/analysis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Cells , Case-Control Studies , Drug Resistance, Neoplasm , Female , Humans , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Neoplasm Proteins/analysis , Plasma Cells/metabolism , Plasma Cells/pathologyABSTRACT
PURPOSE: Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38- stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML. EXPERIMENTAL DESIGN: BCRP expression (measured flow-cytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38- cells. RESULTS: BCRP was preferentially expressed in leukemic CD34+38- cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38- cells. CONCLUSIONS: These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broad-spectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.
