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J. Biol. Chem., Vol. 283, Issue 8, 4501-4511, February 22, 2008

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Inhibition of Multidrug Resistance by AdamantylGb₃, a Globotriaosylceramide Analog^*

María Fabiana De Rosa^¶**1, Cameron Ackerley, Bernice Wang^||, Shinya Ito^||, David M. Clarke^**, and Clifford Lingwood^¶2

From the Division of Molecular Structure and Function, Department of Pediatric Laboratory Medicine, and Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario M5G 1X8 and the ^¶Department of Laboratory Medicine and Pathobiology, ^||Departments of Pediatrics and Pharmacology, and ^**Departments of Medicine and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Multidrug resistance (MDR) via the ABC drug transporter (ABCB1), P-glycoprotein (P-gp/MDR1) overexpression, is a major obstacle in cancer chemotherapy. Many inhibitors reverse MDR but, like cyclosporin A (CsA), have significant toxicities. MDR1 is also a translocase that flips glucosylceramide inside the Golgi to enhance neutral glycosphingolipid (GSL) synthesis. We observed partial MDR1/globotriaosylceramide (Gb₃) cell surface co-localization, and GSL removal depleted cell surface MDR1. MDR1 may therefore interact with GSLs. AdamantylGb₃, a water-soluble Gb₃ mimic, but not other GSL analogs, reversed MDR1-MDCK cell drug resistance. Cell surface MDR1 was up-regulated 1 h after treatment with CsA or adaGb₃, but at 72 h, cell surface expression was lost. Intracellular MDR1 accumulated throughout, suggesting long term defects in plasma membrane MDR1 trafficking. AdaGb₃ or CsA rapidly reduced rhodamine 123 cellular efflux. MDR1 also mediates gastrointestinal epithelial drug efflux, restricting oral bioavailability. Vinblastine apical-to-basal transport in polarized human intestinal C2BBe1 cells was significantly increased when adaGb₃ was added to both sides, or to the apical side only, comparable with verapamil, a standard MDR1 inhibitor. Disulfide cross-linking of mutant MDR1s showed no binding of adaGb₃ to the MDR1 verapamil/cyclosporin-binding site between surface proximal helices of transmembrane segments (TM) 6 and TM7, but rather to an adjacent site nearer the center of TM6 and the TM7 extracellular face, i.e. close to the bilayer leaflet interface. Verotoxin-mediated Gb₃ endocytosis also up-regulated total MDR1 and inhibited drug efflux. Thus, a functional interplay between membrane Gb₃ and MDR1 provides a more physiologically based approach to MDR1 regulation to increase the bioavailability of chemotherapeutic drugs.

Received for publication, July 3, 2007 , and in revised form, November 9, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Grants MT 13073 (to C. A. L.) and MT 13747 (to S. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Restracomp training studentship from The Hospital for Sick Children.

² To whom correspondence should be addressed. Fax: 416-813-5993; E-mail: cling{at}sickkids.ca.

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