Liposomal Delivery Enhances Short-Chain Ceramide-Induced Apoptosis of Breast Cancer Cells
- 1 November 2003
- journal article
- Published by Elsevier in The Journal of Pharmacology and Experimental Therapeutics
- Vol. 307 (2) , 468-475
- https://doi.org/10.1124/jpet.103.054056
Abstract
It is therapeutically desirable to effectively deliver ceramide, an antimitogenic and proapoptotic lipid second messenger, to transformed cell types. However, the targeted delivery of cell-permeable ceramide analogs, including C6-ceramide, to cells may be impeded by the hydrophobicity of these bioactive lipids, resulting in reduced efficacy. The objective of this study is to develop and optimize liposomal vehicles to augment ceramide delivery to a breast adenocarcinoma cell line. We designed conventional, cationic, and pegylated drug release vesicles to efficaciously deliver ceramide to MDA-MB-231 breast adenocarcinoma cells. In vitro pharmacokinetic analysis demonstrated that liposomal ceramide delivery resulted in significantly greater accumulation of ceramide in MDA-MB-231 cells. Ceramide-formulated liposomes significantly inhibited MDA-MB-231 cell proliferation as compared with nonliposomal administration of ceramide. Ceramide-induced apoptosis correlated with the pharmacokinetic profile and the diminished proliferation in this highly aggressive, metastatic cell line. Liposomal ceramide formulations inhibited phosphorylated Akt levels and stimulated caspase-3/7 activity more effectively than nonliposomal ceramide, events consistent with apoptosis. Together, these results indicate that bioactive ceramide analogs can be incorporated into conventional, cationic, or pegylated liposomal vehicles for improved drug delivery and release.Keywords
This publication has 43 references indexed in Scilit:
- Exchange of C16-Ceramide between Phospholipid VesiclesBiochemistry, 1999
- Sphingomyelinase Induces Lipid Microdomain Formation in a Fluid Phosphatidylcholine/Sphingomyelin MembraneBiochemistry, 1998
- Inhibition of Akt Kinase by Cell-permeable Ceramide and Its Implications for Ceramide-induced ApoptosisPublished by Elsevier ,1998
- Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiationCell Death & Differentiation, 1998
- Measurement of Spontaneous Transfer and Transbilayer Movement of BODIPY-Labeled Lipids in Lipid VesiclesBiochemistry, 1997
- Sphingolipids—The Enigmatic Lipid Class: Biochemistry, Physiology, and PathophysiologyToxicology and Applied Pharmacology, 1997
- Ceramide synthase mediates daunorubicin-induced apoptosis: An alternative mechanism for generating death signalsCell, 1995
- Ceramide Prevents Neuronal Programmed Cell Death Induced by Nerve Growth Factor DeprivationJournal of Neurochemistry, 1995
- Induction of apoptotic DNA fragmentation and cell death by natural ceramideFEBS Letters, 1995
- Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.The Journal of Experimental Medicine, 1994