BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells.
We have previously described a mitoxantrone-resistant MCF7 cell line that is cross-resistant to topotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11), and 9-aminocamptothecin, but not to camptothecin. A novel mechanism that resulted in decreased topotecan accumulation in MCF7/MX cells was proposed (Yang et al. Cancer Res 55: 4004-4009, 1995). We now have developed a topotecan-resistant cancer cell line from wild-type MCF7 cells. MCF7/TPT300 cells were 68.9-fold resistant to topotecan, 68.3-fold to 10-hydroxy-7-ethylcamptothecin (SN-38), and 116-fold to mitoxantrone, but only 4.1-fold to camptothecin. Topotecan efflux was increased in MCF7/TPT300 cells compared with MCF7/WT cells, and this increase was reversed upon ATP depletion by sodium azide, suggesting an energy-dependent drug efflux mechanism. However, MCF7/TPT300 cells did not overexpress P-glycoprotein or the multidrug resistance-associated protein (MRP1). In contrast, overexpression of the breast cancer resistance protein (BCRP/MXR/ABCP) was observed in MCF7/TPT300 cells as well as DNA topoisomerase I down-regulation. Our data suggest that enhanced topotecan efflux contributes partly to topotecan resistance in MCF7/TPT300 cells, possibly mediated by BCRP/MXR/ABCP.
Department of Oncology, National Taiwan University Hospital and the Graduate Institute of Medicine, Medical College, National Taiwan University, Taipei. chjyang@ha.mc.ntu.edu.tw
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D019772:Topotecan; C116614:ABCG2 protein, human; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1