Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia.
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.
Liu
Xin
X
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA. Xliu2@hmc.psu.edu
Ryland
Lindsay
L
Yang
Jun
J
Liao
Aijun
A
Aliaga
Cesar
C
Watts
Rebecca
R
Tan
Su-Fern
SF
Kaiser
James
J
Shanmugavelandy
Sriram S
SS
Rogers
Andrew
A
Loughran
Kathleen
K
Petersen
Bailey
B
Yuen
Jonathan
J
Meng
Fanxue
F
Baab
Kendall Thomas
KT
Jarbadan
Nancy Ruth
NR
Broeg
Kathleen
K
Zhang
Ranran
R
Liao
Jason
J
Sayers
Thomas Joseph
TJ
Kester
Mark
M
Loughran
Thomas P
TP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D008081:Liposomes / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D012074:Remission Induction; D000077022:Survivin; D016896:Treatment Outcome
C516989:Birc5 protein, rat; D002518:Ceramides; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases