Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1074/jbc.M404466200

Type

Journal article

Journal

J Biol Chem

Publication Date

24/09/2004

Volume

279

Pages

40412 - 40418

Keywords

1-Deoxynojirimycin, Antineoplastic Agents, Phytogenic, Cell Line, Tumor, Ceramides, Chromatography, High Pressure Liquid, Chromatography, Thin Layer, Dose-Response Relationship, Drug, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Enzyme Inhibitors, Flow Cytometry, Glucosamine, Glucosylceramides, Glucosyltransferases, Glycolipids, Humans, Imino Sugars, Lipids, Morpholines, P-Glycoprotein, P-Glycoproteins, Quinolines, Time Factors, Vinblastine