Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts

Abstract

For more than 40 years, the fluid mosaic model of cellular membranes have supported our vision of an inert lipid bilayer containing membrane protein receptors that are randomly hit by extracellular molecules to trigger intracellular signaling events. However, the notion that compartmentalized cholesterol- and sphingomyelin-rich membrane microdomains known as lipid rafts spatially arrange receptors and effectors to promote kinetically favorable interactions necessary for signal transduction sounds much more realistic. Despite of their assumed importance in the dynamics of ligand-receptor interactions, lipid rafts and biomembranes as a whole remain less investigated than other classes of biomolecules because of the high variability and complexity of the phases of membranes, which rarely provide detailed atomic-level structural data in x-ray crystallography studies. The fact that some alkylphospholipids, namely edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) can selectively induce the apoptotic death of cancer cells by recruiting Fas death receptors and downstream signaling molecules into clusters of lipid rafts demonstrates that these potential drug targets deserve a more in-depth investigation. However, Phase II clinical studies have demonstrated that edelfosine has only a tumorostatic effect in humans, and not a cytotoxic action as it would be desirable for an antitumor drug. Therefore, herein we propose to synthesize edelfosine analogues that retain the ability to accumulate in lipid rafts, aiming the selective induction of apoptosis in tumor cells. The designed analogues will have their cytotoxic activities evaluated "in vitro" and, if an increase of the anti-neoplastic activity was achieved, they will be also tested "in vivo". (AU)