Reversal of heavy metal resistance in multidrug-resistant human KB carcinoma cells

Biochem Biophys Res Commun. 1997 Jul 30;236(3):586-90. doi: 10.1006/bbrc.1997.7015.


Human KB carcinoma C-A120 cells that express multidrug resistance-associated protein (MRP) were cross-resistant to trivalent and pentavalent antimonials and arsenicals. Intracellular glutathione (GSH) content was higher in C-A120 than its parental KB-3-1 cell line. Glutathione-S-transferase (GST) was similar in both cell lines. Depletion of cellular GSH by treatment of the cells with the inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), buthione sulfoximine (BSO), significantly increased the sensitivity of both KB-3-1 and C-A120 cells to heavy metals. A pyridine analog, PAK-104P, almost completely reversed the resistance to antimonials and arsenicals in C-A120 cells. BSO at 100 microM or PAK-104P at 10 microM enhanced the accumulation of antimony potassium tartrate in C-A120 cells to the level of that in KB-3-1 cells without the agents. PAK-104P inhibited the ATP-dependent efflux of antimony potassium tartrate. These findings suggest that MRP transports antimony conjugated with GSH ATP-dependently outside the cells and PAK-104P inhibits the transporting activity of MRP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / pharmacology
  • Antimony / metabolism
  • Antimony / pharmacology
  • Antimony Potassium Tartrate / metabolism
  • Arsenic / pharmacology
  • Buthionine Sulfoximine / pharmacology
  • Cyclic P-Oxides / pharmacology
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Glutamate-Cysteine Ligase / antagonists & inhibitors
  • Glutathione / metabolism
  • Glutathione Transferase / metabolism
  • Humans
  • KB Cells
  • Metals, Heavy / pharmacology*
  • Multidrug Resistance-Associated Proteins
  • Nicotinic Acids / pharmacology


  • ATP-Binding Cassette Transporters
  • Cyclic P-Oxides
  • Enzyme Inhibitors
  • Metals, Heavy
  • Multidrug Resistance-Associated Proteins
  • Nicotinic Acids
  • PAK 104P
  • Buthionine Sulfoximine
  • Adenosine Triphosphate
  • Antimony
  • Antimony Potassium Tartrate
  • Glutathione Transferase
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Arsenic