title: Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia.
abstract: Abstract Natural killer (NK) cell leukemia is characterized by clonal expansion of CD3 - NK cells and comprises both chronic and aggressive forms. Currently no effective treatment exists, thus providing a need for identification of novel therapeutics. Lipidomic studies revealed a dysregulated sphingolipid metabolism as evidenced by decreased levels of overall ceramide species and increased levels of cerebrosides in leukemic NK cells, concomitant with increased glucosylceramide synthase (GCS) expression. GCS, a key enzyme of this pathway, neutralizes pro-apoptotic ceramide by transfer of a uridine diphosphate (UDP)-glucose. Thus, we treated both rat and human leukemic NK cells in combination with: (1) exogenous C6-ceramide nanoliposomes in order to target mitochondria and increase physiological pro-apoptotic levels of long chain ceramide, and (2) 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), an inhibitor of GCS. Co-administration of C6-ceramide nanoliposomes and PPMP elicited an increase in endogenous long-chain ceramide species, which led to cellular apoptosis in a synergistic manner via the mitochondrial intrinsic cell death pathway in leukemic NK cells.
authors.affiliation: Penn State Hershey Cancer Institute, Pennsylvania State College of Medicine, Hershey, PA 17033-0850, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Watters
authors.forename: Todd E
authors.initials: TE
authors.lastname: Fox
authors.forename: Su-Fern
authors.initials: SF
authors.lastname: Tan
authors.forename: Sriram
authors.initials: S
authors.lastname: Shanmugavelandy
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Choby
authors.forename: Kathleen
authors.initials: K
authors.lastname: Broeg
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000494:pharmacology; D000077022:Survivin
chemical_list: C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002518:Ceramides; D004338:Drug Combinations; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; C579095:MCL1 protein, human; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017382:Reactive Oxygen Species; D013107:Sphingolipids; D000077022:Survivin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase