Oncology Drug Targets in the Sphingomyelin-Signaling Pathway

Publisher Summary This chapter provides an overview of recent advances in targeting sphingosyl- lysophospholipids (LPLs) to provide treatments for cancer. Sphingosyl-LPLs include sphingomyelins, ceramides, sphingosines and sphingosine-1-phosphate. They are ubiquitous membrane components of essentially all eukaryotic cells and are abundantly located in all plasma membranes as well as in some intracellular organelles (endoplasmic reticulum, Golgi complex and mitochondria). Sphingomyelin-associated sphingosyl-LPLs are of particular interest in anti-cancer therapy because of three metabolites of sphingomyelin: ceramide and sphingosine are potent inducers of apoptosis and produce cell cycle arrest, whereas sphingosine-1-phosphate is anti-apoptotic and promotes cell growth and migration. Thus, the metabolism of sphingomyelin generates signal molecules important to the modulation of cell growth and proliferation, differentiation and apoptosis (cell survival)—processes critical to the progression of cancer and resistance to cancer therapy. Understanding the biochemistry of LPLs is complicated by the bewildering combination of specific head groups including head groups containing various carbohydrates and hydrocarbon (fatty acid) tails often assigned the same general name, for example, ceramide. The reason for this structural diversity is not understood however is likely significant with respect to biologic function.