title: Inhibition of glucosylceramide synthase does not reverse drug resistance in cancer cells.
abstract: 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.
authors.affiliation: Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Norris-Cervetto
authors.forename: Richard
authors.initials: R
authors.lastname: Callaghan
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005963:Glucosylceramides / Q000737:chemistry; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars; D008055:Lipids / Q000737:chemistry; D009025:Morpholines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D006017:Glycolipids; D050111:Imino Sugars; D008055:Lipids; D009025:Morpholines; D011804:Quinolines; C478942:n-(n-nonyl)-deoxygalactonojirimycin; D017485:1-Deoxynojirimycin; D014747:Vinblastine; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; C402343:tariquidar; D005944:Glucosamine