Reversal of heavy metal resistance in multidrug-resistant human KB carcinoma cells.
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.
Chen
Z S
ZS
Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Japan.
Mutoh
M
M
Sumizawa
T
T
Furukawa
T
T
Haraguchi
M
M
Tani
A
A
Akiyama
S
S
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000965:Antimony / Q000378:metabolism / Q000494:pharmacology; D000966:Antimony Potassium Tartrate / Q000378:metabolism; D001151:Arsenic / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003498:Cyclic P-Oxides / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D019216:Metals, Heavy / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000965:Antimony; D000966:Antimony Potassium Tartrate; D001151:Arsenic; D019328:Buthionine Sulfoximine; D003498:Cyclic P-Oxides; D004791:Enzyme Inhibitors; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005982:Glutathione Transferase; D019216:Metals, Heavy; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009539:Nicotinic Acids; C103821:PAK 104P