Document Detail

The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs.
MedLine Citation:
PMID:  12692077     Owner:  NLM     Status:  MEDLINE    
Conversion of ceramide, a putative mediator of anticancer drug-induced apoptosis, into glucosylceramide, by the action of glucosylceramide synthase (GCS), has been implicated in drug resistance. Herein, we compared GM95 mouse melanoma cells deficient in GCS activity, with cells stably transfected with a vector encoding GCS (GM95/GCS). Enzymatic and metabolic analysis demonstrated that GM95/GCS cells expressed a fully functional enzyme, resulting in normal ceramide glycosylation. However, cytotoxicity assays, as well as caspase activation and cytochrome c release studies, did not reveal any difference between the two cell lines with respect to their sensitivity toward doxorubicin, vinblastine, paclitaxel, cytosine arabinoside, or short-chain ceramide analogs. Administration of doxorubicin resulted in ceramide accumulation in both cell lines, with similar kinetics and amplitude. Although glucosylceramide formation was detected in doxorubicin-treated GM95/GCS cells, metabolism of drug-induced ceramide did not appear to be instrumental in cell survival. Furthermore, N-(n-butyl)deoxynojirimycin, a potent and non-toxic GCS inhibitor, had no chemosensitizing effect on wild-type melanoma cells. Altogether, both genetic and pharmacological alterations of the cellular ceramide glycosylation capacity failed to sensitize melanoma cells to anticancer drugs, therefore moderating the importance of ceramide glucosylation in drug-resistance mechanisms.
Robert Jan Veldman; Alain Mita; Olivier Cuvillier; Virginie Garcia; Karin Klappe; Jeffrey A Medin; John D Campbell; Stéphane Carpentier; Jan Willem Kok; Thierry Levade
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Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2003-04-08
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  17     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-05-29     Completed Date:  2003-06-25     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1144-6     Citation Subset:  IM    
INSERM U.466, Laboratoire de Biochimie, Institut Louis Bugnard, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France.
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MeSH Terms
ATP-Binding Cassette Transporters / analysis
Antineoplastic Agents / pharmacology,  therapeutic use
Cell Survival
Ceramides / biosynthesis,  pharmacology
Doxorubicin / pharmacology
Drug Resistance, Neoplasm*
Gene Deletion
Glucosyltransferases / antagonists & inhibitors*,  genetics,  metabolism
Melanoma, Experimental / drug therapy*,  enzymology,  pathology
Models, Biological
Tumor Cells, Cultured
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents; 0/Ceramides; 23214-92-8/Doxorubicin; EC 2.4.1.-/Glucosyltransferases; EC glucosyltransferase

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