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Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice
F Dahm1, A Bielawska, A Nocito
1Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Rämistrasse 100, Zurich CH-8091, Switzerland.
Abstract:
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.
Insights
This study shows the ceramide analogue LCL-30 effectively targets mitochondria in colorectal cancer cells, reducing tumor growth in vivo. LCL-30 demonstrates efficacy and safety, warranting further investigation for improved delivery methods.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Sphingolipids, particularly ceramide, regulate cell fate in both normal and cancerous cells.
- Mitochondria are critical in ceramide-mediated cell death pathways.
- The ceramide analogue LCL-30 demonstrated in vitro cell death induction via mitochondrial targeting.
Purpose of the Study:
- To evaluate the efficacy and safety of LCL-30 in an in vivo model of colorectal cancer.
- To investigate the pharmacokinetic properties and mitochondrial accumulation of LCL-30 in vivo.
- To explore the impact of LCL-30 on cellular energy metabolism and sphingolipid profiles in tumors.
Main Methods:
- Administration of LCL-30 to murine colorectal cancer cell line CT-26 in vitro and in vivo.
- Mitochondrial ceramide and sphingosine-1-phosphate (S1P) levels were analyzed.
- ATP content, cytotoxicity, and tumor growth rates were measured.
- Pharmacokinetic analysis of LCL-30 absorption, distribution, and clearance in mice.
Main Results:
- LCL-30 accumulated in mitochondria of CT-26 cells, reducing ATP content and causing dose-dependent cytotoxicity.
- In vivo, LCL-30 reduced tumor proliferative activity and growth rate.
- Elevated S1P levels were observed in mitochondria and tumor tissues.
- LCL-30 showed rapid absorption and clearance but dose-limiting peritoneal toxicity.
Conclusions:
- LCL-30 is the first long-chain pyridinium ceramide applied in vivo for experimental metastatic colorectal cancer treatment.
- LCL-30 demonstrated significant anti-tumor efficacy and an acceptable safety profile in this model.
- Further research is needed to optimize LCL-30 administration and identify combination therapies.
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