An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells

Exp Cell Res. 1998 May 1;240(2):312-20. doi: 10.1006/excr.1998.3938.


The mechanism for cisplatin resistance in cisplatin-resistant KCP-4 cells was studied. Although multidrug resistance-associated protein (MRP) was not detected in KCP-4 cells, the cells were more resistant to heavy metals than multidrug-resistant C-A120 cells that overexpressed MRP. KCP-4 cells expressed metallothionein, but it was scarcely involved in cisplatin resistance in these cells. KCP-4 cells did not express canalicular multispecific organic anion transporter (cMOAT). The glutathione (GSH) level was 4.7-fold higher in KCP-4 cells than in KB-3-1 cells. When the GSH level in KCP-4 cells was decreased by treating the cells with buthionine sulfoximine and nitrofurantoin, the accumulation of and sensitivity to cisplatin in the cells were increased. C-A120 cells were only 3.0-fold more resistant to cisplatin than KB-3-1 cells and this resistance was not affected by the increased glutathione level. The accumulation of platinum in C-A120 and KCP-4 cells was 68.5 and 20.4% of that in KB-3-1 cells, respectively, while the intracellular levels of antimony potassium tartrate in C-A120 and KCP-4 cells were 13.2 and 9.9% of that in KB-3-1 cells, respectively. The ATP-dependent efflux of antimony was enhanced in both C-A120 and KCP-4 cells. These results, taken together, suggest an efflux pump for heavy metals different from MRP and cMOAT is involved in cisplatin resistance in KCP-4 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis
  • Anion Transport Proteins
  • Buthionine Sulfoximine / pharmacology
  • Carrier Proteins / biosynthesis
  • Cisplatin / pharmacology*
  • DNA, Complementary
  • Drug Resistance, Multiple*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Humans
  • Metallothionein / biosynthesis
  • Metals, Heavy*
  • Multidrug Resistance-Associated Proteins
  • Nitrofurantoin / pharmacology
  • Tartrates / pharmacology
  • Transfection
  • Tumor Cells, Cultured


  • ATP-Binding Cassette Transporters
  • Anion Transport Proteins
  • Carrier Proteins
  • DNA, Complementary
  • Metals, Heavy
  • Multidrug Resistance-Associated Proteins
  • Tartrates
  • Buthionine Sulfoximine
  • Metallothionein
  • Nitrofurantoin
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Cisplatin
  • tartaric acid