title: Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia.
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.
authors.affiliation: Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA. Xliu2@hmc.psu.edu
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Lindsay
authors.initials: L
authors.lastname: Ryland
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Aijun
authors.initials: A
authors.lastname: Liao
authors.forename: Cesar
authors.initials: C
authors.lastname: Aliaga
authors.forename: Rebecca
authors.initials: R
authors.lastname: Watts
authors.forename: Su-Fern
authors.initials: SF
authors.lastname: Tan
authors.forename: James
authors.initials: J
authors.lastname: Kaiser
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Shanmugavelandy
authors.forename: Andrew
authors.initials: A
authors.lastname: Rogers
authors.forename: Kathleen
authors.initials: K
authors.lastname: Loughran
authors.forename: Bailey
authors.initials: B
authors.lastname: Petersen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yuen
authors.forename: Fanxue
authors.initials: F
authors.lastname: Meng
authors.forename: Kendall Thomas
authors.initials: KT
authors.lastname: Baab
authors.forename: Nancy Ruth
authors.initials: NR
authors.lastname: Jarbadan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Broeg
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhang
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Thomas Joseph
authors.initials: TJ
authors.lastname: Sayers
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
mesh_terms: 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
chemical_list: C516989:Birc5 protein, rat; D002518:Ceramides; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases