Sphingolipids, which include
ceramides and
sphingosine, are essential structural components of cell membranes that also have messenger functions that regulate the proliferation, survival, and death of cells. Exogenous application of
ceramide is cytotoxic, and exposure of cells to radiation or
chemotherapy is associated with increased
ceramide levels due to enhanced de novo synthesis, catabolism of
sphingomyelin, or both.
Ceramide can be metabolized to less toxic forms by glycosylation, acylation, or by catabolism to
sphingosine, which is then phosphorylated to the anti-apoptotic
sphingosine 1-phosphate.
Glucosylceramide synthase overexpression has been shown to enhance resistance to
doxorubicin, suggesting that inhibition of
ceramide metabolism or catabolism might enhance
cancer chemotherapy. Several
anticancer agents, including the cytotoxic
retinoid,
fenretinide (4-HPR), have been shown to act, at least in part, by increasing
tumor cell
ceramide via de novo synthesis. Combinations of
4-HPR and modulators of
ceramide action and/or metabolism demonstrated increased anti-
tumor activity in pre-clinical models with minimal toxicity for non-malignant cells, and were effective in a p53-independent manner against tumor cell lines resistant to standard
cytotoxic agents. Phase I trials of
ceramide metabolism inhibitors in combination with
4-HPR and with other
cytotoxic agents are in development. Thus, pharmacological manipulation of
sphingolipid metabolism to enhance
tumor cell
ceramide is being realized and offers a novel approach to
cancer chemotherapy.