An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein

Br J Cancer. 1995 Sep;72(3):535-42. doi: 10.1038/bjc.1995.370.


We have characterised an etoposide-resistant subline of the small-cell lung cancer cell line, UMCC-1, derived at our centre. Subline UMCC-1/VP was developed by culturing the parent line in increasing concentrations of etoposide over 16 months. UMCC-1/VP is 20-fold resistant to etoposide by MTT assays, relative to the parent line, and is cross-resistant to doxorubicin, vincristine and actinomycin D, but not to taxol, cisplatin, melphalan, thiotepa or idarubicin. Topoisomerase II immunoblotting demonstrates a 50% reduction of the protein in the resistant subline. The UMCC-1/VP subline demonstrates a marked decrease in the accumulation of [3H]etoposide relative to the parent line, as well as a modest reduction in the accumulation of daunorubicin. Reverse transcription-polymerase chain reaction assays demonstrate no detectable mdr1 expression but marked expression of the multidrug resistance-associated protein (MRP) gene in the resistant subline. Northern blotting with an MRP cDNA probe confirms marked overexpression of the MRP gene only in the UMCC-1/VP subline. Western blotting with antisera against MRP peptide confirms a 195 kDa protein band in the UMCC-1/VP subline. Southern blotting experiments demonstrate a 10-fold amplification of the MRP gene in the resistant subline. Depletion of glutathione with buthionine sulphoximine sensitised UMCC-1/VP cells to daunorubicin and etoposide. Our studies indicate that MRP gene expression may be induced by etoposide and may lead to reduced accumulation of the drug.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology*
  • DNA Topoisomerases, Type II / metabolism
  • Drug Resistance
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Multiple / physiology
  • Etoposide / pharmacokinetics
  • Etoposide / pharmacology*
  • Gene Expression
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / metabolism
  • Middle Aged
  • Multidrug Resistance-Associated Proteins
  • Phenotype
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Membrane Proteins
  • Multidrug Resistance-Associated Proteins
  • Topoisomerase II Inhibitors
  • Etoposide
  • DNA Topoisomerases, Type II