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

Abstract

1 Glibenclamide, a sulphonylurea widely used for the treatment of non-insulin-dependent diabetes mellitus, has been shown to inhibit the activities of various ATP-binding cassette (ABC) transporters. In the present study, its e ects towards multidrug resistance protein 1 (MRP1), an ABC e ux pump conferring multidrug resistance and handling organic anions, were investigated. 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-related calcein e ux. By contrast, glibenclamide did not alter calcein levels in parental control GLC4 cells. Another sulphonylurea, tolbutamide, was however without e ect on calcein accumulation in both GLC4/Sb30 and GLC4 cells. 3 Glibenclamide used at 12.5 mM was, moreover, found to strongly enhance the sensitivity of GLC4/Sb30 cells towards vincristine, an anticancer drug handled by MRP1. 4 E ux of carboxy-2',7'-dichloro¯uorescein, an anionic dye handled by the ABC transporter MRP2 sharing numerous substrates with MRP1 and expressed at high levels in liver, was also strongly inhibited by glibenclamide in isolated rat hepatocytes. 5 In summary, glibenclamide reversed MRP1-mediated drug resistance likely through inhibiting MRP1 activity and blocked organic anion e ux from MRP2-expressing hepatocytes. Such e ects associated with the known inhibitory properties of glibenclamide towards various others ABC proteins suggest that this sulphonylurea is a general inhibitor of ABC transporters.

Effects of Sulfonylureas on Tumor Growth: A Review of the Literature

“…Furthermore, intracellular accumulation of vincristine, another MRP1 substrate, was shown, and this indicates that glibenclamide might act as a sensitizer of cancer cells to chemotherapeutic agents. Even though the MRP1-inhibiting dosage of the sulfonylurea might preclude its clinical application, these results confirm its role as a general ABC transporter inhibitor [24].…”

“…Glibenclamide seems to directly bind and block MRP at higher concentrations than those permitted in affected patients without toxicity [24].…”

“…A first step toward better knowledge of glibenclamide's mechanism of action was achieved by a French group investigating its role as inhibitor of adenosine triphosphate-binding cassette (ABC) transporters [24].…”

Vacuolar Transport of Abscisic Acid Glucosyl Ester Is Mediated by ATP-Binding Cassette and Proton-Antiport Mechanisms in Arabidopsis

“…This indicated the existence of an additional, energized ABA-GE transport mechanism. The addition of the known ABC transporter inhibitor orthovanadate (1 mM) or glibenclamide (0.1 mM; Martinoia et al, 1993;Payen et al, 2001) likewise reduced the ABA-GE uptake activity, by 26% or 51%, respectively. Combining the inhibitors of ABC transporters and V-ATPases, orthovanadate and bafilomycin A1, resulted in 50% reduction of the ABA-GE uptake activity.…”

Tetrandrine enhances cytotoxicity of cisplatin in human drug-resistant esophageal squamous carcinoma cells by inhibition of multidrug resistance-associated protein 1

“…In addition, MRP1 can even shift drugs out of cells into the extracellular fluid by vesicle transportation or exocytosis (14,18,19). Numerous studies have shown that inhibition of MRP1 expression by a variety of methods eased the development of drug resistance, thus supported clinical chemotherapy (20)(21)(22). Regarding the expression of MRP1 in esophageal cancer, it has been demonstrated that MRP1 often overexpressed in different esophageal cancer cell lines or cancer tissues of patients (23)(24)(25).…”