AN ACTIVE EFFLUX SYSTEM FOR HEAVY-METALS IN CISPLATIN-RESISTANT HUMANKB CARCINOMA-CELLS

The mechanism for cisplatin resistance in cisplatin-resistant KCP-4 ce lls was studied. Although multidrug resistance-associated protein (MRP ) was not detected in KCP-4 cells, the cells were more resistant to he avy metals than multidrug-resistant C-A120 cells that overexpressed MR P, KCP-4 cells expressed metallothionein, but it was scarcely involved in cisplatin resistance in these cells. KCP-4 cells did not express c analicular multispecific organic anion transporter (cMOAT), The glutat hione(GSH) level was 4.7-fold higher in KCP-4 cells than in KB-3-1 cel ls. When the GSH level in KCP-4 cells was decreased by treating the ce lls with buthionine sulfoximine and nitrofurantoin, the accumulation o f and sensitivity to cispaltin in the cells were increased. C-A120 cel ls were only 3.0-fold more resistant to cisplatin than KB-3-1 cells an d 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 2 0.4% of that in KB-3-1 cells, respectively, while the intracellular le vels 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 ef flux of antimony was enhanced in both C-A120 and KCP-4 cells. These re sults, taken together, suggest an efflux pump for heavy metals differe nt from MRP and cMOAT is involved in cisplatin resistance in KCP-4 cel ls. (C) 1998 Academic Press.