Rapid Distribution of Liposomal Short-Chain Ceramide in Vitro and in Vivo

Zolnik, Banu S.; Stern, Stęphan T.; Kaiser, James; Heakal, Yasser; Clogston, Jeffrey D.; Kester, Mark; McNeil, Scott E.

doi:10.1124/dmd.107.019679

Cited by 75 publications

(87 citation statements)

References 23 publications

(39 reference statements)

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“…The neoplasm-selectivity exhibited by C 6 -ceramide is probably due to biophysical mechanism by which nanoliposomal C 6 -ceramide exhibits a bilayer exchange mechanism, which circumvents the lysosomal degradation pathway and allows for immediate distribution of C 6 -ceramide to well-perfused cancer tissue. 39 It is of interest that nanoliposome C 6 ceramide had some biologic activity even in animals showing progression of leukemia, as evidenced by decreased white blood cell (blast) counts compared with control animals ( Figure 5B). We speculate that variability in leukemia burden at time of initiation of ceramide nanoliposomal therapeutics was a contributing factor to the inability to obtain complete remission in all animals.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Ryland

Yang

et al. 2010

Blood

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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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Section: Discussionmentioning

confidence: 99%

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

Liu

Ryland

Yang

et al. 2010

Blood

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“…Reported antitumor effects resulting from targeted inhibition of ceramide metabolizing enzymes include induction of apoptosis [16,17], growth inhibition [17][18][19], and increased sensitivity to radiation [20] and chemotherapeutics [21,22]. Use of exogenous, cell-permeable ceramide analogs, C6-and C8-cer, has also demonstrated promising anti-cancer activity in preclinical studies [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Flowers

Fabriás

Delgado

et al. 2011

Breast Cancer Res Treat

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The sphingolipid ceramide is known to play a central role in chemo- and radiation-induced cell death. Acid ceramidase (AC) hydrolyzes ceramide, and thus reduces intracellular levels of this proapoptotic lipid. The role of AC as a putative anticancer target is supported by reports of upregulation in prostate cancer and in some breast tumors. In this study, we determined whether the introduction of an AC inhibitor would enhance the apoptosis-inducing effects of C6-ceramide (C6-cer) in breast cancer cells. Cultured breast cancer cells were treated with DM102 [(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide, C6-cer, or the combination. Cell viability and cytotoxic synergy were assessed. Activation of apoptotic pathways, generation of reactive oxygen species, and mitochondrial transmembrane potential were determined. DM102 was a more effective AC inhibitor than N-oleoylethanolamine (NOE) and (1R,2R)-2-N-(tetradecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol (B-13) in MDA-MB-231, MCF-7, and BT-474 cells. As single agents, C6-cer (IC(50) 5-10 μM) and DM102 (IC(50) 20 μM) were only moderately cytotoxic in MDA-MB-231, MCF-7, and SK-BR-3 cells. Co-administration, however, produced synergistic decreases in viability (combination index <0.5) in all cell lines. Apoptosis was confirmed in MDA-MB-231 cells by detection of caspase 3 cleavage and a >3-fold increase in caspase 3/7 activation, PARP cleavage, and a >70% increase in Annexin-V positive cells. C6-cer/DM102 increased ROS levels 4-fold in MDA-MB-231 cells, shifted the ratio of Bax:Bcl-2 to >9-fold that of control cells, and resulted in mitochondrial membrane depolarization. DM102 also increased the synthesis of (3)H-palmitate-labeled long-chain ceramides by 2-fold when C6-cer was present. These data support the effectiveness of targeting AC in combination with exogenous short-chain ceramide as an anticancer strategy, and warrant continued investigation into the utility of the C6-cer/DM102 drug duo in human breast cancer.

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“…24,25 Furthermore, the C6-ceramide nanoliposomal formulation has been extensively characterized by the Nanotechnology Characterization Laboratory of the National Cancer Institute and most importantly was shown to be free of toxic side effects associated with other anti-neoplastic agents. 26 ROS production was restored in both U-87 MG and LN-18 glioblastoma cells when targeted by siRNA directed against GCS, but not a non-targeted siRNA ( Fig. 3B and C).…”

Section: Resultsmentioning

confidence: 99%

“…These results showed that targeting GCS, the enzyme responsible for neutralizing ceramide and synthesizing NOX-impeding glucosylceramide, augmented agents has drawn some criticism due to issues with solubility, specificity or toxicity, we employed the more direct approach, the molecular targeting of GCS utilizing siRNA. 26 An important aspect of our approach was the use of a non-toxic cationic nanoliposomal delivery method. Typical cationic transfection reagents are impractical for in vivo use due to severe toxicity.…”

Section: Resultsmentioning

confidence: 99%