BCRP transports dipyridamole and is inhibited by calcium channel blockers.
OBJECTIVE
We investigated whether dipyridamole and various calcium channel blockers are inhibitors and/or substrates of breast cancer resistance protein (BCRP).


METHODS
The effect of dipyridamole and the calcium channel blockers on mitoxantrone efflux by BCRP-overexpressing human embryonic kidney (HEK) cells was determined by flow cytometry. The ability of some of these compounds to reverse BCRP-mediated mitoxantrone resistance was measured by cytotoxicity assays. Transport studies were performed using radiolabeled compounds.


RESULTS
Dipyridamole, nicardipine, nitrendipine, and nimodipine effectively inhibited BCRP-mediated mitoxantrone efflux; however, bepridil, diltiazem, and verapamil had no significant effect. Nifedipine is a much weaker BCRP inhibitor compared with other dihydropyridines tested. Nicardipine and dipyridamole were the most potent BCRP inhibitors among the compounds tested with IC50 values of 4.8 +/- 1.3 and 6.4 +/- 0.9 microM, respectively. Nicardipine and dipyridamole also effectively reversed BCRP-mediated mitoxantrone resistance in HEK cells. [3H]Nitrendipine was found not to be transported by BCRP. However, the transport of [3H]dipyridamole by BCRP was observed in both HEK and Madin-Darby canine kidney cells stably expressing the transporter, and this transport was completely abolished by fumitremorgin C, a known BCRP inhibitor.


CONCLUSIONS
Dipyridamole and several dihydropyridines are effective BCRP inhibitors, but bepridil, diltiazem, and verapamil are not. We also identified a new BCRP substrate, dipyridamole.
Zhang
Yi
Y
Department of Pharmaceutics, School of Pharmacy, University of Washington, Box 357610, Seattle, Washington 98195-7610, USA.
Gupta
Anshul
A
Wang
Honggang
H
Zhou
Lin
L
Vethanayagam
R Robert
RR
Unadkat
Jashvant D
JD
Mao
Qingcheng
Q
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001693:Biological Transport, Active; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology; D004176:Dipyridamole / Q000378:metabolism*; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009568:Nitrendipine / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009363:Neoplasm Proteins; D010975:Platelet Aggregation Inhibitors; D004176:Dipyridamole; D009568:Nitrendipine; D008942:Mitoxantrone