Defining the role of MRP-mediated efflux and glutathione in detoxification of oxaliplatin.
Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gü83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance.
Department of Clinical Pharmacy, University of Bonn, Germany.
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Mohn
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Häcker
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RA
Hilger
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M
Gütschow
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U
Jaehde
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000633:toxicity; D000077150:Oxaliplatin; D010984:Platinum / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1