Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells.

Abstract

Ceramides are sphingolipid second messengers that are involved in the mediation of cell death. There is accumulating evidence that mitochondria play a central role in ceramide-derived toxicity. We designed a novel cationic long-chain ceramide [omega-pyridinium bromide D-erythro-C16-ceramide (LCL-30)] targeting negatively charged mitochondria. Our results show that LCL-30 is highly cytotoxic to SW403 cells (and other cancer cell lines) and preferentially accumulates in mitochondria, resulting in a decrease of the mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-3 and caspase-9. Ultrastructural analyses support the concept of mitochondrial selectivity. Interestingly, levels of endogenous mitochondrial C16-ceramide decreased by more than half, whereas levels of sphingosine-1-phosphate increased dramatically and selectively in mitochondria after administration of LCL-30, suggesting the presence of a mitochondrial sphingosine kinase. Of note, intracellular long-chain ceramide levels and sphingosine-1-phosphate remained unaffected in the cytosolic and extramitochondrial (nuclei/cellular membranes) cellular fractions. Furthermore, a synergistic effect of cotreatment of LCL-30 and doxorubicin was observed, which was not related to alterations in endogenous ceramide levels. Cationic long-chain pyridinium ceramides might be promising new drugs for cancer therapy through their mitochondrial preference.

• Authors: Daniel Dindo, Felix Dahm, Zdzislaw Szulc, Alicja Bielawska, Lina M Obeid, Yusuf A Hannun, Rolf Graf, Pierre-Alain Clavien
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 6 Pg. 1520-9 (Jun 2006) ISSN: 1535-7163 [Print] United States
• PMID: 16818511 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cations
• Ceramides
• Drug Combinations
• Lysophospholipids
• sphingosine 1-phosphate
• N-palmitoylsphingosine
• Doxorubicin
• Cytochromes c
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• Caspases
• Sphingosine

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Caspase 3
• Caspase 9
• Caspases (metabolism)
• Cations
• Cell Death (drug effects)
• Ceramides (chemistry, pharmacology)
• Colonic Neoplasms (drug therapy, metabolism)
• Cytochromes c (metabolism)
• Doxorubicin (pharmacology)
• Drug Combinations
• Drug Synergism
• Enzyme Activation (drug effects)
• Humans
• Lysophospholipids (metabolism)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membranes (drug effects)
• Sphingosine (analogs & derivatives, metabolism)
• Tumor Cells, Cultured (ultrastructure)