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BCRP Transports Dipyridamole and is Inhibited by Calcium Channel Blockers

Purpose

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 μM, 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.

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Abbreviations

ABC:

ATP-binding cassette

BCRP:

breast cancer resistance protein

DMSO:

dimethyl sulfoxide

FTC:

fumitremorgin C

HEK:

human embryonic kidney cells

mAb:

monoclonal antibody

MDCK:

Madin–Darby canine kidney

MRP1:

multidrug resistance protein 1

MRP2:

multidrug resistance protein 2

MX:

mitoxantrone

P-gp:

P-glycoprotein

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Acknowledgments

The authors acknowledge financial support from NIH grant HD044404 (to QM and JDU) and from the Department of Pharmaceutics, University of Washington. We thank Dr. Robert W. Robey and Dr. Susan E. Bates (National Cancer Institute, Bethesda, MD, USA) for providing the pcDNA-482R plasmid, FTC, and the HEK cell lines. We also thank Dr. Alberto Lazarowski (Clinical Chemistry Laboratory, Instituto de Investigaciones Neurológicas “Raul Carrea,” Buenos Aires, Argentina) for his useful comments in the initial stage of this study.

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Zhang, Y., Gupta, A., Wang, H. et al. BCRP Transports Dipyridamole and is Inhibited by Calcium Channel Blockers. Pharm Res 22, 2023–2034 (2005). https://doi.org/10.1007/s11095-005-8384-4

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Key Words

  • BCRP
  • dipyridamole and calcium channel blockers
  • inhibition
  • substrate