Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice.
The sphingolipid ceramide is intimately involved in the growth, differentiation, senescence, and death of normal and cancerous cells. Mitochondria are increasingly appreciated to play a key role in ceramide-induced cell death. Recent work showed the C16-pyridinium ceramide analogue LCL-30 to induce cell death in vitro by mitochondrial targeting. The aim of the current study was to translate these results to an in vivo model. We found that LCL-30 accumulated in mitochondria in the murine colorectal cancer cell line CT-26 and reduced cellular ATP content, leading to dose- and time-dependent cytotoxicity. Although the mitochondrial levels of sphingosine-1-phosphate (S1P) became elevated, transcription levels of ceramide-metabolising enzymes were not affected. In mice, LCL-30 was rapidly absorbed from the peritoneal cavity and cleared from the circulation within 24 h, but local peritoneal toxicity was dose-limiting. In a model of subcutaneous tumour inoculation, LCL-30 significantly reduced the proliferative activity and the growth rate of established tumours. Sphingolipid profiles in tumour tissue also showed increased levels of S1P. In summary, we present the first in vivo application of a long-chain pyridinium ceramide for the treatment of experimental metastatic colorectal cancer, together with its pharmacokinetic parameters. LCL-30 was an efficacious and safe agent. Future studies should identify an improved application route and effective partners for combination treatment.
Dahm
F
F
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Rämistrasse 100, Zurich CH-8091, Switzerland.
Bielawska
A
A
Nocito
A
A
Georgiev
P
P
Szulc
Z M
ZM
Bielawski
J
J
Jochum
W
W
Dindo
D
D
Hannun
Y A
YA
Clavien
P-A
PA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002518:Ceramides / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D045304:Cytochromes c / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D015394:Molecular Structure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D002518:Ceramides; C527436:D-erythro-2-N-(160-(1''-pyridinium)hexadecanoyl)sphingosine bromide; D013107:Sphingolipids; D045304:Cytochromes c; D020169:Caspases; D013110:Sphingosine