An Active Efflux System for Heavy Metals in Cisplatin-Resistant Human KB Carcinoma Cells |
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Authors: | Zhe-Sheng Chen Masato Mutoh Tomoyuki Sumizawa Tatsuhiko Furukawa Misako Haraguchi Ayako Tani Nagahiro Saijo Takahito Kondo Shin-Ichi Akiyama |
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Affiliation: | aDepartment of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890, Japan;bBasic Research Laboratories, Toray Industries, Inc. Tebiro 1111, Kamakura, Kanagawa, 248, Japan;cPharmacology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104, Japan;dDepartment of Pathological Biochemistry, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, 852, Japan |
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Abstract: | 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 cispaltin 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. |
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Keywords: | cisplatin resistance GS-X pump GSH MRP cMOAT |
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