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Research Articles: Therapeutics

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

¹ Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland; ² Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina; and ³ Research Service, Department of Veterans Affairs Medical Center, Charleston, South Carolina

Requests for reprints: Pierre-Alain Clavien, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Phone: 41-1-255-33-00; Fax: 41-1-255-44-49. E-mail: clavien{at}chir.unizh.ch

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 [-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. [Mol Cancer Ther 2006;5(6):1520–9]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: D. Dindo and F. Dahm contributed equally to this work.

⁴ Z. Szulc and A. Bielawska, in preparation.

⁵ J. Bielawski, Z.M. Szulc, Y.A. Hannun, and A. Bielawska. Methods. In press 2005.

Received 12/12/05; revised 4/ 5/06; accepted 4/21/06.