Differential Expression of DNA Topoisomerase II Alpha and -Beta in P-gp and MRP-negative VM26, mAMSA and Mitoxantrone-Resistant Sublines of the Human SCLC Cell Line GLC4

Br J Cancer. 1996 Dec;74(12):1869-76. doi: 10.1038/bjc.1996.647.

Abstract

Sublines of the human small-cell lung carcinoma (SCLC) cell line GLC4 with acquired resistance to teniposide, amsacrine and mitoxantrone (GLC4/VM20x, GLC4/AM3x and GLC4/MIT60x, respectively) were derived to study the contribution of DNA topoisomerase II alpha and -beta (TopoII alpha and -beta) to resistance for TopoII-targeting drugs. The cell lines did not overexpress P-glycoprotein or the multidrug resistance-associated protein but were cross-resistant to other TopoII drugs. GLC4/VM20x showed a major decrease in TopoII alpha protein (54%; for all assays presented in this paper the GLC4 level was defined to be 100%) without reduction in TopoII beta protein; GLC4/AM3x showed only a major decrease in TopoII beta protein (to 18%) and not in TopoII alpha. In GLC4/MIT60x, the TopoII alpha and -beta protein levels were both decreased (TopoII alpha to 31%; TopoII beta protein was undetectable). The decrease in TopoII alpha protein in GLC4/VM20x and GLC4/MIT60x, was mediated by decreased TopoII alpha mRNA levels. Loss of TopoII alpha gene copies contributed to the mRNA decrease in these cell lines. Only in the GLC4/MIT60x cell line was an accumulation defect observed for the drug against which the cell line was made resistant. In conclusion, TopoII alpha and -beta levels were decreased differentially in the resistant cell lines, suggesting that resistance to these drugs may be mediated by a decrease in a specific isozyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP-Binding Cassette Transporters / analysis*
  • Amsacrine / pharmacology
  • Antigens, Neoplasm / biosynthesis*
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / metabolism*
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II* / biosynthesis*
  • DNA-Binding Proteins
  • Drug Resistance, Multiple*
  • Humans
  • In Situ Hybridization, Fluorescence / methods
  • Isoenzymes / biosynthesis*
  • Isoenzymes / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Mitoxantrone / pharmacology
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger / analysis
  • RNA, Neoplasm / analysis
  • Teniposide / pharmacology
  • Tumor Cells, Cultured

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Isoenzymes
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Amsacrine
  • Teniposide
  • Mitoxantrone
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II