Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines.
The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any of the cell lines. In addition, we have transfected the MRP1 gene into an intrinsically cisplatin-resistant cell line SKOV3, previously shown to have elevated levels of glutathione (GSH). The MRP1-transfected line SKOV3-S2 was shown to be cross-resistant to doxorubicin, vincristine and etoposide but not to paclitaxel, vinblastine and platinum agents, such as cisplatin, JM216 [bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II)]. No cross-resistance to any of the platinum agents was observed in a MRP1-overexpressing human lung cancer cell line with acquired doxorubicin resistance. Reduction of GSH levels (80-90%) by buthionine sulphoximine (BSO) produced significant potentiation in cisplatin sensitivity in the parental SKOV3, the vector-alone control SKOV3-puro and the MRP1-transfected line SKOV3-S2. The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4.1-fold) but not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV3-puro and the SKOV3-S2 cells, although both these transfected lines accumulated significantly more than the parental line. Our results suggest that MRP1 does not play a significant role in platinum resistance in the human tumour cell lines investigated in this study.
CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
S Y
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Sharp
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Smith
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Hobbs
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Kelland
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D019328:Buthionine Sulfoximine; D002945:Cisplatin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds; D014750:Vincristine; C110525:amminedichloro(2-methylpyridine)platinum(II); C081294:satraplatin