Characterization of the Contribution of Ceramide to Chemotherapy Sensitization in Breast Cancer Cells

摘要

Our previous studies showed that the drug resistance modulator, PSC 833, increased cellular ceramide levels, thus initiating caspase-apoptotic signaling. The mechanism of PSC 833 induced ceramide generation was, however, unknown. In order to use ceramide targeting as a therapeutic approach to chemotherapy sensitization in breast cancer, mechanism information is essential. During the past three years, our studies demonstrate that PSC 833 induces ceramide generation via the de novo biochemical pathway, as opposed to degradation of sphingomyelin. We have shown, for the first time, that serine palmitoyltransferase (SPT), and not ceramide synthase is activated by PSC 833. Furthermore, we also demonstrate a close structure-activity relationship for activation of SPT. The research has also shown that PSC 833 induces ceramide generation in a broad spectrum of human breast cancer cell lines. Furthermore, we have demonstrated that SPT is the target enzyme in ceramide generation that is induced by other well known chemotherapeutic drugs, including etoposide, taxol, and retinoids. In combination with a downstream ceramide modulator, PSC 833 greatly elevates ceramide and synergizes chemotherapy- elicited cytotoxicity in breast cancer cells. This is a significant finding which provides a novel approach to breast cancer treatment opening the door for new drug design targeting ceramide metabolism.