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Research ArticleArticle

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

Eleftheria Tsakalozou, Eyob D. Adane, Kuei-Ling Kuo, Abigail Daily, Jeffrey A. Moscow and Markos Leggas
Drug Metabolism and Disposition July 2013, 41 (7) 1404-1413; DOI: https://doi.org/10.1124/dmd.112.050021
Eleftheria Tsakalozou
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Eyob D. Adane
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Kuei-Ling Kuo
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Abigail Daily
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Jeffrey A. Moscow
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Markos Leggas
Department of Pharmaceutical Sciences, College of Pharmacy (E.T., E.D.A., K.-L.K., M.L.), and Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky (A.D., J.A.M.)
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Abstract

AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1- and SLCO1B3-transfected cell systems compared with the mock-transfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.

Footnotes

    • Received November 12, 2012.
    • Accepted April 24, 2013.
  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA-123867].

  • dx.doi.org/10.1124/dmd.112.050021.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (7)
Drug Metabolism and Disposition
Vol. 41, Issue 7
1 Jul 2013
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The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro
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Research ArticleArticle

Impact of Transporters on the Cytotoxicity of AR-67 In Vitro

Eleftheria Tsakalozou, Eyob D. Adane, Kuei-Ling Kuo, Abigail Daily, Jeffrey A. Moscow and Markos Leggas
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1404-1413; DOI: https://doi.org/10.1124/dmd.112.050021

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Research ArticleArticle

Impact of Transporters on the Cytotoxicity of AR-67 In Vitro

Eleftheria Tsakalozou, Eyob D. Adane, Kuei-Ling Kuo, Abigail Daily, Jeffrey A. Moscow and Markos Leggas
Drug Metabolism and Disposition July 1, 2013, 41 (7) 1404-1413; DOI: https://doi.org/10.1124/dmd.112.050021
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