The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2).
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.
Litman
T
T
National Cancer Institute, Medicine Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Brangi
M
M
Hudson
E
E
Fetsch
P
P
Abati
A
A
Ross
D D
DD
Miyake
K
K
Resau
J H
JH
Bates
S E
SE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D026901:Membrane Transport Proteins; D018613:Microscopy, Confocal; D008942:Mitoxantrone / Q000493:pharmacokinetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012269:Ribosomal Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005456:Fluorescent Dyes; D026901:Membrane Transport Proteins; D008942:Mitoxantrone; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1