Cytoprotective effect of glucosylceramide synthase inhibition against daunorubicin-induced apoptosis in human leukemic cell lines.
Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin (DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell lines. We now report that inhibition of glucosylceramide synthase using d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER) significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease) were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts, whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis "protector" (GalCER).
Grazide
Solène
S
INSERM U563-Centre de Physiopathologie Toulouse Purpan, Institut Claudius Régaud, Toulouse 31052, France.
Terrisse
Anne-Dominique
AD
Lerouge
Sandra
S
Laurent
Guy
G
Jaffrézou
Jean-Pierre
JP
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006031:Glycosylation; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D020298:U937 Cells
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009025:Morpholines; D020011:Protective Agents; D003561:Cytarabine; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D003630:Daunorubicin