Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice

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 doselimiting. 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.

Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts

“…Microvascular density of each CD31 stained tumor was counted in 10 random high-power fields (Â400) by two investigators blinded with respect to the experimental group. Mitotic figures and Ki-67 positive nuclei were quantified as previously described (21).…”

Increased tumour dihydroceramide production after Photofrin-PDT alone and improved tumour response after the combination with the ceramide analogue LCL29. Evidence from mouse squamous cell carcinomas

“…LCL124, alone or in combination with the chemotherapeutic agent gemcitabine, inhibits substantially the growth of human head and neck squamous cell carcinomas in vitro and in vivo (Senkal et al, 2006). LCL30 has potent antitumour activity against colorectal cancer in mice (Dahm et al, 2008).…”

“…To overcome the low solubility of ceramide, cationic pyridinium ceramide analogues have been developed, which are water soluble . These analogues have effective anticancer activity at relatively low concentrations (Novgorodov et al, 2005;Rossi et al, 2005;Dindo et al, 2006;Senkal et al, 2006;Zeidan and Hannun, 2007;Dahm et al, 2008). LCL124, alone or in combination with the chemotherapeutic agent gemcitabine, inhibits substantially the growth of human head and neck squamous cell carcinomas in vitro and in vivo (Senkal et al, 2006).…”

LCL124, a Cationic Analog of Ceramide, Selectively Induces Pancreatic Cancer Cell Death by Accumulating in Mitochondria

“…It is reasonable to predict that cationic ceramides would preferentially accumulate in the mitochondria of cancer cells based on their increased negative charge. Indeed, the efficacy of cationic ceramides on tumor regression has been confirmed in multiple tumor models (Novgorodov et al, 2005;Senkal et al, 2006;Dahm et al, 2008). Specifically, LCL29 and 124 (D-e-and L-t-stereoisomers of C6-CCPS) (Senkal et al, 2006;Szulc et al, 2006) have been shown to have antiproliferative effects in MCF7 and head and neck squamous cell carcinoma (HNSCC) cell lines (Rossi et al, 2005).…”