The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by
sphingolipid cancer research. Many studies have shown that
ceramide generation in response to
cytotoxic agents is central to
tumor cell death.
Ceramide can be generated either via hydrolysis of cell-membrane
sphingomyelin by sphingomyelinases, hydrolysis of
cerebrosides, or via de novo synthesis by
ceramide synthases.
Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the
sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the
acid ceramidase can lead to the formation of
sphingosine 1-phosphate, which then antagonizes
ceramide signaling by initiating a pro-survival signaling pathway. Furthermore,
ceramide glycosylation catalyzed by
glucosylceramide synthase converts
ceramide to
glucosylceramide, thus eliminating
ceramide and consequently protecting
cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on
ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents.