The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

TY - JOUR

T1 - The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

AU - Litman, Thomas

AU - Brangi, M

AU - Hudson, E

AU - Fetsch, P

AU - Abati, A

AU - Ross, D D

AU - Miyake, K

AU - Resau, J H

AU - Bates, S E

N1 - The first confocal study of substrates of ABCG2

PY - 2000/6

Y1 - 2000/6

N2 - Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown. We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glycoprotein-mediated multidrug resistance. Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance. Definition of its mechanism of transport and its role in clinical oncology is required.

AB - Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown. We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glycoprotein-mediated multidrug resistance. Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance. Definition of its mechanism of transport and its role in clinical oncology is required.

KW - ATP-Binding Cassette Transporters

KW - Antineoplastic Agents

KW - Blotting, Northern

KW - Breast Neoplasms

KW - Colonic Neoplasms

KW - DNA-Binding Proteins

KW - Drug Resistance, Multiple

KW - Drug Resistance, Neoplasm

KW - Fluorescent Dyes

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunohistochemistry

KW - Membrane Transport Proteins

KW - Microscopy, Confocal

KW - Mitoxantrone

KW - Multidrug Resistance-Associated Proteins

KW - P-Glycoprotein

KW - Polymerase Chain Reaction

KW - RNA, Messenger

KW - Ribosomal Proteins

KW - Tumor Cells, Cultured

KW - ABCG2

KW - ABCG2/BCRP

KW - MXR

M3 - Journal article

C2 - 10806112

SN - 0021-9533

VL - 113 ( Pt 11)

SP - 2011

EP - 2021

JO - Journal of Cell Science

JF - Journal of Cell Science

ER -