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. 2006 Jun;5(6):1520-9.
doi: 10.1158/1535-7163.MCT-05-0513.

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

Daniel Dindo  1 , Felix Dahm, Zdzislaw Szulc, Alicja Bielawska, Lina M Obeid, Yusuf A Hannun, Rolf Graf, Pierre-Alain Clavien
Affiliations

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

Daniel Dindo et al. Mol Cancer Ther. 2006 Jun.

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.

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