The anticancer peptide LL-III alters the physico-chemical properties of a model tumor membrane promoting lipid bilayer permeabilization.

LL-III is an anticancer peptide and has the ability to translocate across tumor cell membranes, which indicates that its action mechanism could be non-membranolytic. However, the exact mechanism through which the peptide gains access into the cell cytoplasm is still unknown. Here, we use a plethora of physico-chemical techniques to characterize the interaction of LL-III with liposomes mimicking the lipid matrix of the tumor cell membrane and its effect on the microstructure and thermotropic properties of the membrane. Furthermore, the effect of the presence of Ca 2+ cations at physiological concentration was also investigated. For comparison, the interaction of LL-III with liposomes mimicking the normal cell membrane was also studied. Our results show that the peptide selectively interacts with the model tumor cell membrane. This interaction does not disrupt the lipid bilayer but deeply alters its properties by promoting lipid lateral reorganization and increasing membrane permeability. Overall, our data provide a molecular level description of the interaction of the peptide with the model tumor membrane and are fully consistent with the non-membranolytic action mechanism.