Affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
The bioactive sphingolipid, ceramide, has garnered major interest as a principle regulator of cellular stress, proliferation, senescence, and death. Of particular interest to cancer biologists and clinical oncologist, dysregulated ceramide metabolism has been documented in both solid and non-solid malignancies. Moreover, most anticancer chemotherapeutics stimulate ceramide accumulation through increased ceramide synthesis or through the inhibition of ceramide catabolism. In fact, neutralization of ceramide via glycosylation or phosphorylation in malignant cells has been linked to multidrug chemoresistance. New therapeutic strategies to overcome chemoresistance focus on increasing endogenous ceramide levels by stimulating ceramide synthesis, by inhibiting ceramide neutralization, or by the direct delivery of exogenous ceramide. This review will discuss new therapeutic strategies designed specifically to modulate ceramide metabolism, as well as nanoscale delivery systems engineered to selectively deliver ceramide to cancerous cells and tissues.