| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cancer Therapy: Preclinical |
1 Leukemia Section, Department of Medicine, 2 Program of Molecular Pharmacology and Cancer Therapeutics, and 3 Cancer Prevention & Population Sciences, Roswell Park Cancer Institute, Buffalo, New York
Requests for reprints: Maria R. Baer, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-5975; Fax: 716-845-8446; E-mail: maria.baer{at}roswellpark.org.
Purpose: Overexpression of the multidrug resistance proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) is associated with treatment failure in acute myeloid leukemia (AML) and other malignancies. The Pgp modulator cyclosporin A has shown clinical efficacy in AML, whereas its analogue PSC-833 has not. Cyclosporin A is known to also modulate MRP-1, and we hypothesized that broad-spectrum multidrug resistance modulation might contribute to its clinical efficacy.
Experimental Design: We studied the effects of cyclosporin A and PSC-833 on in vitro drug retention and cytotoxicity in resistant cell lines overexpressing Pgp, MRP-1, and BCRP and on nuclear-cytoplasmic drug distribution and cytotoxicity in cells overexpressing LRP. Cellular drug content was assessed by flow cytometry and nuclear-cytoplasmic drug distribution by confocal microscopy.
Results: Cyclosporin A enhanced retention of the substrate drug mitoxantrone in cells overexpressing Pgp (HL60/VCR), MRP-1 (HL60/ADR), and BCRP (8226/MR20, HEK-293 482R) and increased cytotoxicity 6-, 4-, 4-, and 3-fold, respectively. Moreover, cyclosporin A enhanced nuclear distribution of doxorubicin in 8226/MR20 cells, which also express LRP, and increased doxorubicin cytotoxicity 12-fold without an effect on cellular doxorubicin content, consistent with expression of wild-type BCRP, which does not efflux doxorubicin. Cyclosporin A also enhanced nuclear doxorubicin distribution in a second cell line with LRP overexpression, HT1080/DR4. PSC-833 enhanced mitoxantrone retention and cytotoxicity in cells overexpressing Pgp, but had no effect in cells overexpressing MRP-1, BCRP, or LRP.
Conclusions: Cyclosporin A modulates Pgp, MRP-1, BCRP, and LRP, and this broad-spectrum activity may contribute to its clinical efficacy.
Key Words: P glycoprotein • multidrug resistance protein • breast cancer resistance protein • lung resistance protein • PSC-833
This article has been cited by other articles:
|
|
 |
|
  S. Hauswald, J. Duque-Afonso, M. M. Wagner, F. M. Schertl, M. Lubbert, C. Peschel, U. Keller, and T. Licht Histone Deacetylase Inhibitors Induce a Very Broad, Pleiotropic Anticancer Drug Resistance Phenotype in Acute Myeloid Leukemia Cells by Modulation of Multiple ABC Transporter Genes Clin. Cancer Res., June 1, 2009; 15(11): 3705 - 3715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zheng, J. E. Koblinski, L. V. Dutson, Y. B. Feeney, and C. V. Clevenger Prolyl Isomerase Cyclophilin A Regulation of Janus-Activated Kinase 2 and the Progression of Human Breast Cancer Cancer Res., October 1, 2008; 68(19): 7769 - 7778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Brand, P. A. I. van der Wel, M. J. Rein, D. Barron, G. Williamson, P. J. van Bladeren, and I. M. C. M. Rietjens Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers Drug Metab. Dispos., September 1, 2008; 36(9): 1794 - 1802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Shen, S. Chu, A. K. Bence, B. Bailey, X. Xue, P. A. Erickson, M. H. Montrose, W. T. Beck, and L. C. Erickson Quantitation of Doxorubicin Uptake, Efflux, and Modulation of Multidrug Resistance (MDR) in MDR Human Cancer Cells J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 95 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, M. R. Baer, M. J. Bowman, P. Pera, X. Zheng, J. Morgan, R. A. Pandey, and A. R. Oseroff The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2 Clin. Cancer Res., April 15, 2007; 13(8): 2463 - 2470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Q. Xia, N. Liu, G. T. Miwa, and L.-S. Gan Interactions of Cyclosporin A with Breast Cancer Resistance Protein Drug Metab. Dispos., April 1, 2007; 35(4): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-A. Esteve, M. Carre, V. Bourgarel-Rey, A. Kruczynski, G. Raspaglio, C. Ferlini, and D. Braguer Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine. Mol. Cancer Ther., November 1, 2006; 5(11): 2824 - 2833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H.G.P. Raaijmakers, E. P.L.M. de Grouw, B. A. van der Reijden, T. J.M. de Witte, J. H. Jansen, and R. A.P. Raymakers ABCB1 Modulation Does Not Circumvent Drug Extrusion from Primitive Leukemic Progenitor Cells and May Preferentially Target Residual Normal Cells in Acute Myelogenous Leukemia. Clin. Cancer Res., June 1, 2006; 12(11): 3452 - 3458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Walter, J. L. Pirga, M. R. Cronk, S. Mayer, F. R. Appelbaum, and D. E. Banker PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism Blood, November 15, 2005; 106(10): 3584 - 3593. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
