Glutathione S-transferases in wild-type and doxorubicin-resistant MCF-7 human breast cancer cell lines

Xenobiotica. 1999 Feb;29(2):155-70. doi: 10.1080/004982599238713.

Abstract

1. Overexpression of glutathione S-transferases (GST) in breast cancer cells is hypothesized to be a component of the multifactorial doxorubicin-resistant phenotype. 2. We have characterized the expression of GST enzymes at the catalytic activity, protein and mRNA levels in wild-type MCF-7 (MCF-7/WT) human breast cancer cells and a line selected for resistance to doxorubicin (MCF-7/ADR), with the goal of modulating GST activity to overcome resistance. 3. The MCF-7/ADR cells were 30-65-fold more resistant to doxorubicin than the MCF-7/WT cells. 4. Total cytosolic GST catalytic activity was elevated 23-fold in the MCF-7/ADR cells as compared with the MCF-7/WT cells, and the MCF-7/ADR cells also showed 3-fold increases in catalytic activity toward GST mu and alpha class-selective substrates. Neither cell line showed detectable catalytic activity with a GST mu class-selective substrate. 5. MCF-7/ADR cells showed pronounced overexpression of GST mu protein and GST P1 mRNA in comparison with the wild-type cell line. Neither cell line displayed detectable GST alpha or mu at the protein level. 6. A glutathione analogue that functions as a selective GST alpha inhibitor was more potent at inhibiting total cytosolic GST catalytic activity in the MCF-7/ADR cell line than GST alpha and mu class-selective inhibitory glutathione analogues and the non-selective GST inhibitor ethacrynic acid. 7. The multidrug resistance-associated protein, which can function as a glutathione-conjugate transporter, appeared weakly overexpressed in the MCF-7/ADR cells in comparison with the MCF-7/WT cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Adenocarcinoma / enzymology
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / enzymology*
  • Catalysis
  • Cytosol / enzymology
  • Doxorubicin / therapeutic use*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • Glutathione Transferase / metabolism*
  • Humans
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins / metabolism
  • RNA, Messenger / metabolism
  • Tumor Cells, Cultured

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Doxorubicin
  • Glutathione Transferase