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: Rebecca J Watters, Todd E Fox, Su-Fern Tan, Sriram Shanmugavelandy, Jacob E Choby, Kathleen Broeg, Jason Liao, Mark Kester, Myles C Cabot, Thomas P Loughran, Xin Liu
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 54 Issue 6 Pg. 1288-96 (Jun 2013) ISSN: 1029-2403 [Electronic] United States
• PMID: 23181473 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol
• Antineoplastic Agents
• BIRC5 protein, human
• Ceramides
• Drug Combinations
• Inhibitor of Apoptosis Proteins
• Liposomes
• MCL1 protein, human
• Morpholines
• Myeloid Cell Leukemia Sequence 1 Protein
• Reactive Oxygen Species
• Sphingolipids
• Survivin
• Glucosyltransferases
• ceramide glucosyltransferase

Topics

• Antineoplastic Agents (administration & dosage, metabolism)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Ceramides (administration & dosage, metabolism)
• Dose-Response Relationship, Drug
• Drug Combinations
• Glucosyltransferases (antagonists & inhibitors, genetics, metabolism)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Leukemia, Large Granular Lymphocytic (genetics, metabolism)
• Liposomes
• Membrane Potential, Mitochondrial (drug effects)
• Morpholines (pharmacology)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sphingolipids (pharmacology)
• Survivin