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J. Biol. Chem., Vol. 279, Issue 39, 40412-40418, September 24, 2004

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Inhibition of Glucosylceramide Synthase Does Not Reverse Drug Resistance in Cancer Cells^*

Edward Norris-Cervetto, Richard Callaghan, Frances M. Platt, Raymond A. Dwek, and Terry D. Butters¶

From the Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU and the Nuffield Department of Clinical Laboratory Sciences, Level 4, John Radcliffe Hospital, Oxford OX1 3QU, United Kingdom

The multidrug-resistant cancer cell lines NCI/AdR^RES and MES-SA/DX-5 have higher glycolipid levels and higher P-glycoprotein expression than the chemosensitive cell lines MCF7-wt and MES-SA. Inhibiting glycolipid biosynthesis by blocking glucosylceramide synthase has been proposed to reverse drug resistance in MDR cells by causing an increased accumulation of proapoptotic ceramide during treatment of cells with cytotoxic drugs. We treated both multidrug-resistant cell lines with the glucosylceramide synthase inhibitors PDMP (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol), C₉DGJ (N-nonyl-deoxygalactonojirimycin) or C₄DGJ (N-butyl-deoxygalactonojirimycin). PDMP achieved a significant reversal of drug resistance in agreement with previous reports. However, the N-alkylated iminosugars C₉DGJ and C₄DGJ, which are more selective glucosylceramide synthase inhibitors than PDMP, failed to cause any reversal of drug resistance despite depleting glycolipids to the same extent as PDMP. Our results suggest that (a) inhibition of glucosylceramide synthase does not reverse multidrug resistance and (b) the chemosensitization achieved by PDMP cannot be caused by inhibition of glucosylceramide synthase alone.

Received for publication, April 22, 2004 , and in revised form, July 16, 2004.

^* This research was funded by the Medical Research Council (UK), Cancer Research (UK), and Oxford GlycoSciences PLC (UK). 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.

^¶ To whom correspondence should be addressed. Tel.: 44-0-1865-275725; E-mail: terry.butters{at}bioch.ox.ac.uk.

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