BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells

Biochem Pharmacol. 2000 Sep 15;60(6):831-7. doi: 10.1016/s0006-2952(00)00396-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / biosynthesis*
  • ATP-Binding Cassette Transporters / genetics
  • Adenosine Triphosphate / metabolism
  • Antineoplastic Agents / pharmacology
  • Biological Transport
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • DNA Topoisomerases, Type I / biosynthesis
  • DNA Topoisomerases, Type II / biosynthesis
  • DNA-Binding Proteins / biosynthesis
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Multidrug Resistance-Associated Proteins*
  • MutS Homolog 3 Protein
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Topotecan / pharmacology*
  • Tumor Cells, Cultured


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • MSH3 protein, human
  • Multidrug Resistance-Associated Proteins
  • MutS Homolog 3 Protein
  • Neoplasm Proteins
  • Topotecan
  • Adenosine Triphosphate
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • multidrug resistance-associated protein 1