Modulation of doxorubicin cytotoxicity by ethacrynic acid

Int J Cancer. 1996 Nov 4;68(3):333-9. doi: 10.1002/(SICI)1097-0215(19961104)68:3<333::AID-IJC11>3.0.CO;2-9.


Energy-dependent membrane efflux pumps have been implicated in mediating resistance to doxorubicin (DOX). Membrane-transport mechanisms distinct from P-glycoprotein, capable of transporting DOX and glutathione conjugates have been reported in human cells. Since glutathione-conjugate-forming compounds may be candidates for modulating the cytotoxicity of certain anti-neoplastic agents transported by such transport mechanism, the present studies were performed (i) to determine whether ethacrynic acid, a glutathione-conjugate-forming diuretic, can increase DOX cytotoxicity, and (ii) to study the kinetics of DOX transport and its inhibition by the glutathione conjugate of ethacrynic acid (EA-SG) in the H69 human small-cell-lung-cancer cell line and 2 derived DOX-resistant sublines. Our results indicate that more than one DOX transport mechanism may exist in these cell lines, and that glutathione conjugates may be useful for modulating the cytotoxic effects of DOX.

Publication types

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

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antibiotics, Antineoplastic / pharmacology*
  • Biological Transport / drug effects
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Diuretics / pharmacology*
  • Doxorubicin / pharmacokinetics*
  • Doxorubicin / pharmacology*
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Ethacrynic Acid / pharmacology*
  • Glutathione / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Multidrug Resistance-Associated Proteins
  • Tumor Cells, Cultured


  • ATP-Binding Cassette Transporters
  • Antibiotics, Antineoplastic
  • Diuretics
  • Multidrug Resistance-Associated Proteins
  • Doxorubicin
  • Glutathione
  • Ethacrynic Acid