Glibenclamide is well known to interact with the sulphonylurea receptor (SUR) and has been shown more recently to inhibit the
cystic fibrosis transmembrane conductance regulator protein (CFTR), both
proteins that are members of the ABC [
adenosine 5'-triphosphate (
ATP)-binding cassette] transporters. The effect of
glibenclamide and two synthetic sulphonylcyanoguanidine derivatives (dubbed
BM-208 and BM-223) was examined on
P-glycoprotein, the major
ABC transporter responsible for multidrug resistance (MDR) in
cancer cells. To this end, we employed different cell lines that do or do not express
P-glycoprotein, as confirmed by Western blotting: first, a tumour cell line (VBL600) selected from a human T-cell line (CEM) derived from an acute leukaemia; second, an epithelial cell line derived from a rat colonic
adenocarcinoma (CC531(mdr+)) and finally, a non tumour epithelial cell line derived from the proximal tubule of the opossum kidney (OK).
Glibenclamide and the two related derivatives inhibited
P-glycoprotein because firstly, they acutely increased [3H]
colchicine accumulation in
P-glycoprotein-expressing cell lines only; secondly BM-223 reversed the MDR phenomenon, quite similarly to
verapamil, by enhancing the cytotoxicity of
colchicine,
taxol and
vinblastine and thirdly,
BM-208 and BM-223 blocked the photoaffinity-labelling of
P-glycoprotein by [3H]
azidopine. Furthermore,
glibenclamide is itself a substrate for
P-glycoprotein, since the cellular accumulation of [3H]
glibenclamide was low and substantially increased by addition of
P-glycoprotein substrates (e. g.,
vinblastine and
cyclosporine) only in the
P-glycoprotein-expressing cell lines. We conclude that
glibenclamide and two sulphonylcyanoguanidine derivatives inhibit
P-glycoprotein and that sulphonylurea drugs would appear to be general inhibitors of
ABC transporters, suggesting an interaction with some conserved motif.