Journal
LEUKEMIA & LYMPHOMA
Volume 54, Issue 6, Pages 1288-1296Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/10428194.2012.752485
Keywords
NK-LGL leukemia; ceramide; glucosylceramide; PPMP
Categories
Funding
- National Institutes of Health [CA098472, CA133525]
- Penn State Hershey Cancer Institute Startup Fund
- Tobacco Settlement funds
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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 C-6-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 C-6-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.
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