An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells.
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.
Chen
Z S
ZS
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Mutoh
M
M
Sumizawa
T
T
Furukawa
T
T
Haraguchi
M
M
Tani
A
A
Saijo
N
N
Kondo
T
T
Akiyama
S
S
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D027321:Anion Transport Proteins; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis; D002945:Cisplatin / Q000494:pharmacology*; D018076:DNA, Complementary; D018432:Drug Resistance, Multiple; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis; D019216:Metals, Heavy; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009582:Nitrofurantoin / Q000494:pharmacology; D013644:Tartrates / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D019328:Buthionine Sulfoximine; D002352:Carrier Proteins; D002945:Cisplatin; D018076:DNA, Complementary; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D008668:Metallothionein; D019216:Metals, Heavy; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009582:Nitrofurantoin; D013644:Tartrates; C029768:tartaric acid