Abstract
The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C₆-ceramide (C₆) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C₆-ceramide may be a promising therapeutic approach for a fatal leukemia.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis / drug effects
-
Caspases / metabolism
-
Cell Survival / drug effects
-
Ceramides / pharmacology*
-
Ceramides / therapeutic use
-
Disease Models, Animal
-
Down-Regulation / drug effects
-
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
-
Humans
-
Leukemia, Large Granular Lymphocytic / drug therapy
-
Leukemia, Large Granular Lymphocytic / enzymology
-
Leukemia, Large Granular Lymphocytic / pathology
-
Leukemia, Large Granular Lymphocytic / therapy*
-
Leukocytes, Mononuclear / drug effects
-
Leukocytes, Mononuclear / pathology
-
Liposomes / metabolism*
-
Microtubule-Associated Proteins / metabolism*
-
Mitochondria / drug effects
-
Mitochondria / metabolism
-
Nanoparticles / chemistry*
-
Rats
-
Rats, Inbred F344
-
Remission Induction
-
Survivin
-
Treatment Outcome
Substances
-
Birc5 protein, rat
-
Ceramides
-
Liposomes
-
Microtubule-Associated Proteins
-
Survivin
-
Extracellular Signal-Regulated MAP Kinases
-
Caspases