title: Relevance of the salvage pathway to N-hexanoylsphingosine metabolic downregulation in human neurotumor cells: implications for apoptosis.
abstract: N-Hexanoylsphingosine (C6-Cer) is currently being evaluated as an antineoplastic agent, after preclinical studies showing its property to reduce tumor growth. Herein it is reported that the cytotoxic effect of C6-Cer, as observed in CHP-100 neurotumor cells, impinges on its continuous uptake from the culture medium, ensuring maintainance of elevated steady-state intracellular levels, in the face of the rapid metabolic removal. C6-Cer metabolism not only does occur by direct glucosylation but is also relevantly driven by utilization via the sphingosine salvage pathway, leading to accumulation of natural ceramide that, in CHP-100 cells, has been demonstrated to lack apoptotic properties. Upon inhibition of glucosylceramide synthase by D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, previously shown to enhance C6-Cer cytotoxic activity, short-chain ceramide metabolism was partly redirected to the salvage pathway, likely attenuating the chemosensitizing effect of the above-mentioned compound. Elucidation of the metabolic machinery driving C6-Cer recycling via the salvage pathway might thus be relevant for optimization of its therapeutic utilization.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, I-00133 Rome, Italy. spinedi@uniroma2.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Spinedi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000493:pharmacokinetics / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D009025:Morpholines; C101954:N-caproylsphingosine; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase