Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia

Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Blood (Impact Factor: 10.45). 11/2010; 116(20):4192-201. DOI: 10.1182/blood-2010-02-271080
Source: PubMed


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.

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Available from: Su-Fern Tan, Aug 28, 2015
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    • "Many cancer chemotherapies have been shown to generate endogenous ceramide, and when de novo generation of ceramide is inhibited, the cellular response to cytotoxic chemotherapeutic agents decreases [4]. In addition, it has previously been shown that accumulation of endogenous ceramides or exogenous ceramide treatment is more toxic to tumor cells than to normal cells [6,9]. However, the exact mechanism of selectivity is unknown. "
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    ABSTRACT: Ceramide is a sphingolipid metabolite that induces cancer cell death. When C6-ceramide is encapsulated in a nanoliposome bilayer formulation, cell death is selectively induced in tumor models. However, the mechanism underlying this selectivity is unknown. As most tumors exhibit a preferential switch to glycolysis, as described in the "Warburg effect", we hypothesize that ceramide nanoliposomes selectively target this glycolytic pathway in cancer. We utilize chronic lymphocytic leukemia (CLL) as a cancer model, which has an increased dependency on glycolysis. In CLL cells, we demonstrate that C6-ceramide nanoliposomes, but not control nanoliposomes, induce caspase 3/7-independent necrotic cell death. Nanoliposomal ceramide inhibits both the RNA and protein expression of GAPDH, an enzyme in the glycolytic pathway, which is overexpressed in CLL. To confirm that ceramide targets GAPDH, we demonstrate that downregulation of GAPDH potentiates the decrease in ATP after ceramide treatment and exogenous pyruvate treatment as well as GAPDH overexpression partially rescues ceramide-induced necrosis. Finally, an in vivo murine model of CLL shows that nanoliposomal C6-ceramide treatment elicits tumor regression, concomitant with GAPDH downregulation. We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect.
    PLoS ONE 12/2013; 8(12):e84648. DOI:10.1371/journal.pone.0084648 · 3.23 Impact Factor
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    • "C6-ceramide promotes apoptosis in CML-derived K562 cells by a mechanism involving caspase-8 and JNK [59]. Nanoliposomal delivery of exogenous ceramide (C6-ceramide) inhibit NK-LGL leukemia in a rat model and the antiproliferative effect of ceramide is through downregulation of antiapoptotic protein survivin [61]. "
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    ABSTRACT: Apoptosis, also called programmed cell death, is physiologically and pathologically involved in cellular homeostasis. Escape of apoptotic signaling is a critical strategy commonly used for cancer tumorigenesis. Ceramide, a derivative of sphingolipid breakdown products, acts as second messenger for multiple extracellular stimuli including growth factors, chemical agents, and environmental stresses, such as hypoxia, and heat stress as well as irradiation. Also, ceramide acts as tumor-suppressor lipid because a variety of stress stimuli cause apoptosis by increasing intracellular ceramide to initiate apoptotic signaling. Defects on ceramide generation and sphingolipid metabolism are developed for cancer cell survival and cancer therapy resistance. Alternatively, targeting ceramide metabolism to correct these defects might provide opportunities to overcome cancer therapy resistance.
    01/2011; 2011:565316. DOI:10.1155/2011/565316
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    ABSTRACT: The designing of polypeptides with novel conduction properties is important because of the role of proteins in molecular electronics. Ant algorithm which is based on the cooperative interaction between artificial ants has proved to be an effective tool for such designing. It has been used in the present work in combination with simple negative factor counting and inverse iteration methods to study the effect of basis set, electron correlation and hydration on the electronic properties and hence the optimum compositions of polyglycine, polyalanine and polyserine in the most conducting protein chain. The results show clearly that a better basis set and the consideration of correlation decreases the band gap by about 1–3 eV. The optimum solution however remains unaffected. Further, using minimal basis set in the presence of water decreases the band gap by about 2.64 eV and changes the major component of the conducting protein from polyserine to polyalanine.
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