Title:Beyond the "Lock and Key" Paradigm: Targeting Lipid Rafts to Induce the Selective Apoptosis of Cancer Cells
VOLUME: 25 ISSUE: 18
Author(s):Anna Carolina Schneider Alves, Reinaldo Antonio Dias, Luciano Porto Kagami, Gustavo Machado das Neves, Fernando Cidade Torres, Vera Lucia Eifler-Lima, Ivone Carvalho, Carolina de Miranda Silva and Daniel Fabio Kawano*
Affiliation:Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP, Rua Candido Portinari 200, 13083-871 Campinas-SP, Institute of Chemistry, University of Campinas - UNICAMP, Rua Josue de Castro s/n, 13083-970 Campinas-SP, Graduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre-RS, Graduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre-RS, School of Pharmacy, UniRitter Laureate International Universities, Rua Orfanotrofio 55, 91849-440 Porto Alegre-RS, Graduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre-RS, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. do Cafe s/n, 14040- 903 Ribeirao Preto-SP, College of Pharmacy, University of Florida, 6550 Sanger Road, 32827 Orlando- FL, Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP, Rua Candido Portinari 200, 13083-871 Campinas-SP
Keywords:Lipid rafts, apoptosis, alkylphospholipids, cancer, edelfosine, cell membrane.
Abstract:For more than 40 years, the fluid mosaic model of cellular membranes has
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 the signal transduction sounds much more
realistic. Despite their assumed importance for the dynamics of ligand-receptor interactions,
lipid rafts and biomembranes as a whole remain less explored than the other classes
of biomolecules because of the higher variability and complexity of their membrane
phases, which rarely provide the detailed atomic-level structural data in X-ray crystallography
assays necessary for molecular modeling studies. The fact that some alkylphospholipids
(e.g. edelfosine: 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) selectively
induce the apoptotic death of cancer cells by recruiting Fas death receptors and the
downstream signaling molecules into clusters of lipid rafts suggests these potential drug
targets deserve a more in-depth investigation. Herein, we review the structure of lipid
rafts, their role in apoptotic signaling pathways and their potential role as drug targets for
the treatment of cancer.
