Suppression of growth, progression and metastasis of breast cancer xenografts by orally administered complex sphingolipids

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Complex sphingolipids in the diet are hydrolyzed in the intestinal cells to bioactive metabolites that significantly reduced early and late stages of colon cancer in rodent models without causing severe side effects. In the present study, we investigated if bioactive metabolites generated from complex sphingolipids supplements can reach distant sites in the body in sufficient concentrations to suppress tumor formation, progression and possibly metastasis. Human breast epithelial cells representing early, intermediate, late and metastatic stages of breast cancer were injected subcutaneously into the mammary fat pad of nude mice. 0.1% sphingomyelin, or a combination with ceramide (0.08% SM, 0.02% ceramide) was added to the diet either before or after tumor implant to test both a preventive and an intervention approach. Orally administered sphingolipids affected tumor number and volume in a stage-dependent manner, with the less aggressive xenografts responding with both lower tumor incidence and tumor volume. This appears to correlate with the rate of proliferation that was more affected in xenografts representing earlier stages of breast cancer. Xenografts of more advanced breast cancer cells responded with a reduction of tumor size only; however, sphingolipid supplements significantly reduced metastases to the lungs (60-73%) and bone marrow (60-84%). These results suggest that sphingolipid supplements target fast growing but less aggressive tumors and metastases while they are relatively ineffective against solid, aggressive but slow growing tumors, indicating a promising potential as chemopreventive agents.
 Supported by grant BCT0503453 from the Susan G. Komen Foundation and NIH/NCI R03 CA101125.