Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel.
The multidrug resistance protein (MRP) family consists of nine members that can be categorized according to whether or not a third (NH(2)-terminal) membrane-spanning domain is present. Three (MRP1, MRP2, and MRP3) of the four members that have this structural feature are able to confer resistance to natural product anticancer agents. We previously established that MRP7, the remaining family member that has three membrane-spanning domains, possesses the cardinal biochemical activity of MRPs in that it is able to transport amphipathic anions such as 17beta-estradiol 17-(beta-d-glucuronide). However, the drug resistance profile of the pump has not been determined. In this study, the drug resistance capabilities of MRP7 are evaluated by analyzing the resistance profiles of two clones of HEK293 cells in which the pump was ectopically expressed. MRP7-transfected HEK293 cells exhibited the highest levels of resistance toward docetaxel (9-13-fold). In addition, lower levels of resistance were observed for paclitaxel (3-fold), vincristine (3-fold), and vinblastine (3-4-fold). Consistent with the operation of an ATP-dependent efflux pump, MRP7-transfected cells exhibited reduced accumulation of radiolabeled paclitaxel compared with HEK293 cells transfected with parental plasmid. These results indicate that MRP7, unlike other MRPs, is a resistance factor for taxanes.
Hopper-Borge
Elizabeth
E
Medical Science Division, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Chen
Zhe-Sheng
ZS
Shchaveleva
Irina
I
Belinsky
Martin G
MG
Kruh
Gary D
GD
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology*; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D043823:Taxoids; C421142:ABCC10 protein, human