Anticancer alpha-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes

摘要

Cancer is a major cause of premature death and there is an urgent need for new anticancer agents with novel mechanisms of action.Here we review recent studies on a group of peptides that show much promise in this regard,exemplified by arthropod cecropins and amphibian magainins and aureins.These molecules are alpha-helical defence peptides,which show potent anticancer activity (alpha-ACPs) in addition to their established roles as antimicrobial factors and modulators of innate immune systems.Generally,alpha-ACPs exhibit selectivity for cancer and microbial cells primarily due to their elevated levels of negative membrane surface charge as compared to non-cancerous eukaryotic cells.The anticancer activity of alpha-ACPs normally occurs at micromolar levels but is not accompanied by significant levels of haemolysis or toxicity to other mammalian cells.Structure / function studies have established that architectural features of alpha-ACPs such as amphiphilicty levels and hydrophobic arc size are of major importance to the ability of these peptides to invade cancer cell membranes.In the vast majority of cases the mechanisms underlying such killing involves disruption of mitochon-drial membrane integrity and / or that of the plasma membrane of the target tumour cells.Moreover,these mechanisms do not appear to proceed via receptor-mediated routes but are thought to be effected in most cases by the carpet / toroidal pore model and variants.Usually,these membrane interactions lead to loss of membrane integrity and cell death utilising apoptic and necrotic pathways.It is concluded that that alpha-ACPs are major contenders in the search for new anticancer drugs,underlined by the fact that a number of these peptides have been patented in this capacity.