Relevance of the Salvage Pathway to N-Hexanoylsphingosine Metabolic Downregulation in Human Neurotumor Cells: Implications for Apoptosis
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.
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Document Type: Research Article
Publication date: March 1, 2012
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- Drug Metabolism Letters publishes short papers on major advances in all areas of drug metabolism and disposition. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly by taking full advantage of the Internet technology for both the submission and review of manuscripts. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites, reactive intermediate and glutathione conjugates.
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