Sphingolipids are critical components of cell membranes. The key building blocks in the formation of the many kinds of sphingolipids are waxes collectively called "ceramides." Ceramides exist in several forms, including as "dihydroceramides". Fenretinide increases toxic dihydroceramide waxes in cancer cells by stimulating their de novo synthesis (i.e., 'from scratch') while simultaneously blocking their conversion to desaturated "ceramides". Safingol resembles the normal precursor molecule of dihydroceramides, called sphinganine. Cancer cells take up and use safingol in place of normal sphinganine which leads to a synergistic toxicity to the cancer cell (a many fold-increase of killing) when used with fenretinide. Fenretinide does not cause dihydroceramide waxes to build up in normal cells. Therefore, fenretinide is not toxic to normal cells and is better-tolerated in patients than many other anticancer agents.
The Synthesis of Ceramide Waxes in Cells
Fenretinide stimulates the synthesis of dihydroceramide waxes in cancer cells but not in normal cells. CerRx Founders have shown that dihydroceramide waxes are toxic to cancer cells.