Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells.
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.
Dindo
Daniel
D
Swiss HPB Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland.
Dahm
Felix
F
Szulc
Zdzislaw
Z
Bielawska
Alicja
A
Obeid
Lina M
LM
Hannun
Yusuf A
YA
Graf
Rolf
R
Clavien
Pierre-Alain
PA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002412:Cations; D016923:Cell Death / Q000187:drug effects*; D002518:Ceramides / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000648:ultrastructure
D000903:Antibiotics, Antineoplastic; D002412:Cations; D002518:Ceramides; D004338:Drug Combinations; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; C097760:N-palmitoylsphingosine; D004317:Doxorubicin; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D013110:Sphingosine