Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia.
Blood 2010 Aug 3; In press
Liu X, Ryland L, Yang J, Liao A, Aliaga C, Watts R, Tan S SF, Kaiser J, Shanmugavelandy S SS, Rogers A, Loughran K, Petersen B, Yuen J, Meng F, Baab K KT, Jarbadan N NR, Broeg K, Zhang R, Liao J, Sayers T TJ, Kester M, Loughran T TP
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA;
The NK type of aggressive LGL leukemia is a fatal illness which 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 C(6)-ceramide (C(6)) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time and dose dependent manner. Importantly, systemic i.v. 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 C(6)-ceramide may be a promising therapeutic approach for a fatal leukemia.
Keywords: survivin nanoliposome ceramide leukemia