The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells

1 Glibenclamide, a sulphonylurea widely used for the treatment of non-insul in-dependent diabetes mellitus, has been shown to inhibit the activities of various ATP-binding cassette (ABC) transporters. In the present study, its effects towards multidrug resistance protein 1 (MRP1), an ABC efflux pump conferring multidrug resistance and handling organic anions, were investiga ted. 2 Intracellular accumulation of calcein: an anionic dye substrate for MRP1, was strongly increased by glibenclamide in a dose-dependent manner in MRP1 -overexpressing lung tumour GLC4/Sb30 cells through inhibition of MRP1-rela ted calcein efflux. By contrast, glibenclamide did not alter calcein levels in parental control GLC4 cells. Another sulphonylurea, tolbutamide, was ho wever without effect on calcein accumulation in both GLC4/Sb30 and GLC4 cel ls. 3 Glibendamide used at 12.5 muM was, moreover, found to strongly enhance th e sensitivity of GLC4/Sb30 cells towards vincristine, an anticancer drug ha ndled by MRP1. 4 Efflux of carboxy-2',7'-dichloroffuorescein, an anionic dye handled by th e ABC transporter MRP2 sharing numerous substrates with MRP1 and expressed at high levels in liver, was also strongly inhibited by glibenclamide in is olated rat hepatocytes. 5 In summary, glibenclamide reversed MRP1-mediated drug resistance likely t hrough inhibiting MRP1 activity and blocked organic anion efflux from MRP2- expressing hepatocytes. Such effects associated with the known inhibitory p roperties of glibenclamide towards various others ABC proteins suggest that this sulphonylurea is a general inhibitor of ABC transporters.