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Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins

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Abstract

Purpose

We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP).

Methods

Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear–cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP.

Results

CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 μM. Tacrolimus enhanced cellular drug uptake at 1 μM, but not at 0.08 μM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 μM, but was effective at its clinically achievable concentration of 0.25 μM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 μM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites.

Conclusions

CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations.

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Acknowledgments

Supported by Grant R21 CA 98457 from the National Cancer Institute and a Leukemia and Lymphoma Society Translational Research Program grant (to MRB), a Cancer and Leukemia Group B Foundation Fellow Grant and an Amgen Oncology Institute Hematology/Oncology Fellowship Grant (to AP), Grant T32 CA 09072-31 from the National Cancer Institute, shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056), the Leonard S. LoVullo Memorial Fund for Leukemia Research and the Dennis J. Szefel Jr. Endowed Fund for Leukemia Research at Roswell Park Cancer Institute and the intramural research program of the NCI, National Institutes of Health, Centre for Cancer Research (to SS and SVA).

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Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Attaphol Pawarode, Hans Minderman, Kieran L. O’Loughlin & Maria R. Baer

  2. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Suneet Shukla & Suresh V. Ambudkar

  3. Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Stacy M. Fricke, Elaine M. Pinder & Maria R. Baer

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  1. Attaphol Pawarode
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Correspondence to Maria R. Baer.

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Pawarode, A., Shukla, S., Minderman, H. et al. Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins. Cancer Chemother Pharmacol 60, 179–188 (2007). https://doi.org/10.1007/s00280-006-0357-8

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