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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / metabolism
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Apoptosis / drug effects*
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Cell Line, Tumor
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Cell Survival / drug effects
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Ceramides / administration & dosage*
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Ceramides / metabolism
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Dose-Response Relationship, Drug
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Drug Combinations
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Glucosyltransferases / antagonists & inhibitors
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Glucosyltransferases / genetics
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Glucosyltransferases / metabolism*
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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Leukemia, Large Granular Lymphocytic / genetics
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Leukemia, Large Granular Lymphocytic / metabolism*
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Liposomes
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Membrane Potential, Mitochondrial / drug effects
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Morpholines / pharmacology
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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Sphingolipids / pharmacology
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Survivin
Substances
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1-phenyl-2-palmitoylamino-3-morpholino-1-propanol
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Antineoplastic Agents
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BIRC5 protein, human
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Ceramides
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Drug Combinations
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Inhibitor of Apoptosis Proteins
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Liposomes
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MCL1 protein, human
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Morpholines
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Myeloid Cell Leukemia Sequence 1 Protein
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Reactive Oxygen Species
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Sphingolipids
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Survivin
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Glucosyltransferases
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ceramide glucosyltransferase